2-naphthyl-carbapenem antibacterial agents

ABSTRACT

Carbapenems of the formula ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by anaphthalene moiety, substituted by various cationic and neutralsubstituents, as described in more detail further below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-naphthyl-carbapenems of the present invention are notcharacterized by a broad antibacterial spectrum such as that ofthienamycin or N-formimidoyl thienamycin. Rather, their spectrum ofactivity is largely limited to gram positive microorganisms, especiallymethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococci (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyof these difficult to control pathogens. Moreover, there is anincreasing need for agents effective against such pathogens (MRSA/MRCNS)which are at the same time safe, i.e., free from undesirable toxic sideeffects. No β-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, there is no description or suggestion of a substituted naphthyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the suprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

EP-A-0277 743 describes a particular class of compounds of the formula:##STR5## but this limited teaching in no way suggests the totallydifferent compounds of the present invention, nor their surprisinglybetter anti-MRSA/MRCNS activity.

SUMMARY OF INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR6## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that one but not more than oneR^(a) is selected from Type I substituents and zero to three R^(a)radicals are selected from Type II substituents; wherein the Type Isubstituents are:

I. (a) ##STR7## where A is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 6and n is 1 to 6 and Q is a covalent bond, O, S, SO, SO₂, NH, --SO₂ NH--,--NHSO₂ --, --CONH--, --NHCO--, --SO₂ N(C₁ -C₄ alkyl)--, --N(C₁ -C₄alkyl)SO₂ --, --CON(C₁ -C₄ alkyl)--, --N(C₁ -C₄ alkyl)CO--, --CH═CH--,--CO--, --OC(O)--, --C(O)O-- or N(C₁ -C₄ alkyl) and (CH₂)_(m) isattached to the naphthyl moiety; ##STR8## is a 5- or 6-memberedmonocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle,the heterocycle containing a first nitrogen in an aromatic 5- or6-membered first ring, with attachment of the heterocycle to A by way ofsaid first nitrogen and said first nitrogen is quaternary by virtue ofthe attachment in addition to the ring bonds thereto, with the firstring containing 0 to 1 of either O or S, with the first ring containing0 to 3 additional nitrogen atoms, with the first ring optionally fusedto a 3- or 4-membered moiety to form the optional second ring, with themoiety containing at least one carbon atom, with the moiety containing 0or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms,and with the moiety being saturated or unsaturated and the second ringaromatic or non-aromatic;

R^(c) is R^(a) as defined under II below, hydrogen, or --NR^(Y) R^(z)(where R^(Y) and R^(z) are defined in II below), but independentlyselected from R^(a) and from each other if more than one R^(c) ispresent, and is attached to a carbon ring atom or a nitrogen heteroatomthe valency of which is not satisfied by the ring bonds;

I. (b) ##STR9## where ##STR10## is a 5- or 6-membered monocyclicheterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, theheterocycle containing a first nitrogen in an aromatic 5- or 6-memberedfirst ring, with said first nitrogen quaternary by virtue of asubstituent R^(d) in addition to the ring bonds thereto, with said firstnitrogen neutral in the absence of a substituent R^(d), with attachmentof the heterocycle to A' by way of a carbon atom of a ring, with thefirst ring containing 0 or 1 of either O or S, with the first ringcontaining 0 to 2 additional nitrogen atoms, with the first ringoptionally fused to a 3- or 4-membered moiety to form the optionalsecond ring, with the moiety containing at least one carbon atom, withthe moiety containing 0 or 1 of either O or S, with the moietycontaining 0 to 2 nitrogen atoms, and with the moiety being saturated orunsaturated and the second ring aromatic or non-aromatic;

R^(c) is as defined above;

R^(d) is hydrogen, NH₂, O⁻ or C₁ -C₄ alkyl (where the alkyl group isoptionally mono-substituted with R^(q) as defined under IIc below);

A' is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 6 and n is 0 to 6, Q isas given above except that when m and n are both 0 then Q is not acovalent bond and (CH₂)_(m) is attached to the naphthyl moiety;

I. (c) --A_(p) --N⁺ R^(y) (R^(w))₀₋₁ (R^(z)) where

R^(y) and R^(z) are as defined under II below,

R^(y) and R^(z) may further be together a C₂ -C₄ alkylidene radical toform a ring (optionally mono-substituted with R^(q) as defined below)interrupted by N(O)R^(e) or N⁺ (R^(e))₂ (where R^(e) is hydrogen, C₁₋₄alkyl, or C₁₋₄ alkyl mono-substituted with R^(q) as defined below),

R^(w) is hydrogen, C₁₋₄ alkyl, O⁻, NH₂ or absent in which case thenitrogen is neutral,

R^(w), R^(y) and R^(z) may further together form a C₅ -C₁₀ tertiaryalkylidene radical which with N⁺ forms a bicyclic ring, where thetertiary alkylidene radical is optionally mono-substituted with R^(q) asdefined below and where the tertiary carbon of the tertiary alkylideneradical is optionally replaced with nitrogen, N⁺ R^(e) (where R^(e) isdefined above), or N⁺ --O⁻,

p is 0 or 1, and

A is as defined above;

I. (d) ##STR11## where ##STR12## is a 5- or 6-membered monocyclicheterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, theheterocycle containing a first nitrogen in a first ring, with the firstring saturated or unsaturated and non-aromatic, with the first nitrogenquaternary by virtue of one or two substituent R^(d) in addition to thering bonds thereto, with the first nitrogen alternatively neutral byvirtue of zero or one substituents R^(d) in addition to the ring bondsthereto, with attachment of the heterocycle to A' by way of a carbonatom or non-quaternary nitrogen atom of a ring, with the first ringcontaining in addition to carbon and the first nitrogen 0 to 1 of amember selected from the group consisting of the non-quaternary nitrogenof attachment, O, S, S(O), S(O)₂ and NR^(e) where R^(e) is as definedabove, with the first ring optionally fused to a 2-, 3- or 4-memberedmoiety to form the optional second ring, with the moiety optionallycontaining in addition to carbon the non-quaternary nitrogen ofattachment, and with the moiety saturated or unsaturated and the secondring non-aromatic;

R^(d) is as defined above and where more than one R^(d) is present on anitrogen, at least one R^(d) is hydrogen or C₁ -C₄ alkyl;

A' is as defined above; and

p is as defined above;

R^(q) is as defined below;

and wherein the Type II substituents are:

II.

(a) a trifluoromethyl group: --CF₃ ;

(b) a halogen atom: --Br, --Cl, --F, or --I;

(c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl isoptionally mono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);

(d) a hydroxy group: --OH;

(e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above;

(f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) where

R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ --, to form a ring(where the ring is optionally mono-substituted with R^(q) as definedabove);

(g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) isdefined above;

(h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

(i) azido: N₃

(j) a formamido group: --N(R^(t))(C═O)H, where

R^(t) is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

(k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

(l) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

(m) a ureido group: --N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

(n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) areas defined above;

(o) a cyano group: --CN;

(p) a formyl or acetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ;

(q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

(r) carbonyl radical: --(C═O)R^(s), where R^(s) is as defined above;

(s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --(C═NOR^(z))R^(y) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

(t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where thealkyl is optionally mono-substituted by R^(q) as defined above;

(u) a carbamoyl radical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) areas defined above;

(v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

(w) a thiocarbamoyl group: --(C═S)N(R^(y))R^(z) where R^(y) and R^(z)are as defined above;

(x) carboxyl: --COOM^(b), where M^(b) is as defined above;

(y) thiocyanate: --SCN;

(z) trifluoromethylthio: --SCF₃ ;

(aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

(ab) an anionic function selected from the group consisting of:phosphono [P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;

(ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in thering is replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄alkyl) and in which one additional carbon atom may be replaced by NH orN(C₁ -C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

(ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above;

(ae) C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents (a) to (ac) above;

(af) C₁ -C₄ alkyl radical;

(ag) C₁ -C₄ alkyl mono-substituted by one of the substituents (a)-(ac)above;

(ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from S and NR^(t) (whereR^(t) is as defined above) and one of the saturated carbon atoms of theoxazolidinone ring is optionally mono-substituted by one of thesubstituents (a) to (ag) above;

M is selected from:

(i) hydrogen;

(ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group;

(iii) an alkali metal or other pharmaceutically acceptable cation; or

(iv) a negative charge which is balanced by a positively charged group.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthesis scheme followed by removal of protecting groups.The objective of the first synthesis stage is to produce a basebromonaphthalene compound which may be converted to the two-positionsubstituent of the carbapenem of Formula I. The objective of the secondsynthesis stage is to attach the base naphthalene to the carbapenem.Finally, the objective of the third synthesis stage is to substitute thenaphthalene with the desired R^(a). This third synthesis stage may beperformed after the first synthesis stage or during or after the secondsynthesis stage according to the nature of the various R^(a).

Flow Sheet A demonstrates a suggested first stage synthesis. Flow SheetsB and C demonstrate two alternative second stage syntheses. The thirdsynthesis varies according to the selected R^(a).

The first synthesis stage, the synthesis of a substitutedbromonaphthalene compound, can be achieved by many processes well-knownin the art. The synthesis, substitution, and elaboration ofnaphthalenes, including bromonaphthalenes, has been thoroughly reviewedin the chemical literature: E. H. Rodd and J. van Alphen in Rodd'sChemistry of Carbon Compounds, Vol. III, Part B, Aromatic Compounds, p.1253 (1956); N. Campbell in Rodd's Chemistry of Carbon Compounds, 2ndEdition, Vol. III, Part G, Aromatic Compounds, p. 99 (1978); M. J. S.Dewar and P. J. Grisdale, J. Am. Chem. Soc., 84, 3541(1962); W. Adcockand P. R. Wells, Aust. J. Chem., 18, 1351(1965); W. Adcock and M.J.S.Dewar, J. Am. Chem Soc., 89, 386(1967); W. Adcock et al., J. Am. Chem.Soc., 97, 2198(1975); E. A. Dixon et al., Can. J. Chem., 59, 2629(1981).Flow Sheet A below shows a representative starting bromonaphthalenecompound, A1.

Employing naphthalene A1, a starting material B1 for the suggestedsecond stage synthesis may be produced. Referring to Flow Sheet A, andstarting with A1, it is first necessary to convert the 1-positioncarboxyl to a desired R^(a) substituent, or a precursor substituentthereto which is stable to the reaction conditions of adding thenaphthalene to a substituted azetidin-2-one precursor of the desiredcarbapenem. A t-butyldimethylsilyloxymethyl precursor substituent may beobtained on the 1-position of A1 in two steps. Firstly, the carboxyl isreduced to hydroxymethyl by reacting A1 with a reducing agent, such aslithium aluminum hydride (LAH), borane, or the like, in a suitable polaraprotic solvent, such as THF, diethyl ether, or the like, at 0° C. toroom temperature (RT). Secondly, the reaction product is isolated andreacted with t-butyldimethylsilyl chloride in dichloromethane withtriethylamine and 4-dimethylaminopyridine to produce protectednaphthalene B1.

As to the R^(a) substituent on compound A1, it may be an R^(a) with orwithout protecting groups stable to the conditions of subsequentlyadding B1 to the carbapenem. Alternatively, it may be a stable precursorsubstituent which is stable to the conditions of making B1, which isoptionally stable to the conditions of adding B1 to the carbapenem andwhich is convertible to a desired R^(a) or to another precursorsubstituent. The identity of the precursor substituent employed is notcrucial so long as it does not interfere with synthesis to B1 and solong as it may be thereafter converted to more desireable substitution.Preferred precursor substituents are methyl, hydroxymethyl and protectedhydroxymethyl.

With stable R^(a) or suitable precursor substituents thereof,naphthalene B1 may be added to azetidin-2-one B2 in a Grignard reactionas shown in Flow Sheet B. The Grignard reaction requires that B1 beconverted to a Grignard reagent by reaction with magnesium and1,2-dibromoethane in a suitable polar aprotic solvent, such as THF,diethyl ether, or the like, from 20° C. to 60° C. and subsequentlycontacting B1 as a Grignard reagent with B2 in a suitable polar aproticsolvent, such as THF, diethyl ether, or the like, at from -70° C. toabout 20° C. to produce azetidin-2-one B3. Alternatively, B1 may bereacted with t-butyllithium, n-butyllithium, or the like in a suitablepolar aprotic solvent, such as THF, diethyl ether, or the like, at from-78° to -50° C. followed by the addition of magnesium bromide to producethe same Grignard reagent. R^(i) of B3 is in practice pyrid-2-yl but mayclearly be a variety of substituents including aromatic andheteroaromatic substituents. Further R^(i) might be for example phenyl,pyrimidinyl or thiazolyl.

Azetidin-2-one B3 is an intermediate that may be ring closed to acarbapenem. It is on this intermediate that R^(a) or precursorsubstituent such as t-butyldimethylsilyloxymethyl should be modifiedwhere such modification is incompatible with the carbapenem nucleus. Forexample, a convenient reaction to remove the t-butyldimethylsilyl groupfrom the 1-position hydroxymethyl substituent of the naphthalene oncompound B3 is to expose compound B3 to a dilute solution of sulfuricacid in methanol at 0° C. Flow Sheet B shows the resulting compound B3A.If the t-butyldimethylsilyl group was removed under the same conditionsafter cyclization of B3 to a carbapenem, a substantial portion ofcarbapenem would be degraded and lost. Thus, modification of theprecursor substituent in this instance and replacement with anotherprecursor substituent or even R^(a) is best performed before closing thecarbapenem. Of course it is possible to remove the t-butyldimethylsilylgroup in reduced yield after cyclization of B3 to a carbapenem byreaction with tetra-n-butylammonium fluoride and acetic acid in THF.

Compound B3A may be ring closed to carbapenem B4 by refluxing in xylenewith a trace of p-hydroquinone for about 1 to 2 hours. It is on thisintermediate that final elaboration of R^(a) from a precursorsubstituent, e.g. hydroxymethyl, may be accomplished. Removal of theprotecting groups then provides the final compound Formula I. Such finalelaboration and deprotection is described in further detail below.##STR13##

Flow Sheet C shows an alternative second stage synthesis, i.e.attachment of the base naphthalene such as B1 to the 2-position of thecarbapenem. This synthesis involves a palladium catalyzed cross-couplingreaction between a carbapenem triflate and a suitably substitutedarylstannane, a process which is described in U.S. patent applicationNo. 485,096 filed Feb. 26, 1990, hereby incorporated by reference. Inorder to apply this synthesis, it is first necessary to modifybromonaphthalene B1 to the trimethylstannylnaphthalene C3. This isaccomplished by reacting B1 with t-butyllithium in THF at from -78° to-50° C. followed by the addition of trimethyltin chloride. This providesan intermediate from which the t-butyldimethylsilyl protecting group onthe 1-position hydroxymethyl substituent is removed by exposure totetra-n-butylammonium fluoride in THF yielding C3. Alternatively,bromonaphthalene B1 may be reacted with hexamethylditin in the presenceof a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium in an inert solvent such astoluene at from 25° to 110° C. for from 0.25 to 24 hours to provide,after removal of the t-butyldimethylsilyl protecting group as describedabove, the same stannane C3. If the t-butyldimethylsilyl group wasremoved under the same conditions after attachment of the naphthaleneside chain to the carbapenem, a much reduced overall yield would beobtained due to degradation of the carbapenem during such a removal.Thus modification of the precursor substituent in this instance andreplacement with another precursor substituent or even R^(a) is bestperformed before attachment to the carbapenem. Referring to Flow SheetC, the 2-oxocarbapenam C1 is reacted with a suitabletrifluoromethanesulfonyl source, such as trifluoromethanesulfonicanhydride, trifluoromethanesulfonyl chloride and the like, in thepresence of an organic nitrogen base, such as triethylamine,diisopropylamine and the like, in polar aprotic solvent, such astetrahydrofuran. An organic nitrogen base, such as triethylamine and thelike, is then added to the reaction solution followed immediately by asilylating agent, such as trimethylsilyl trifluoromethanesulfonate toprovide intermediate C2. An aprotic polar coordinating solvent, such asDMF, 1-methyl-2-pyrrolidinone and the like, is added. This is followedby the addition of a palladium compound, such astris(dibenzylidene-acetone)dipalladium-chloroform, palladium acetate,bis(acetonitrile)palladium(II).chloride and the like, and the stannaneC3. Addition of a suitably substituted arylphosphine, such astris(4-methoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine,trifurylphosphine and the like, may also be beneficial. A metal halide,such as lithium chloride, zinc chloride and the like, is added and thereaction solution is warmed to a suitable temperature, such as 0° to 50°C., and allowed to stir for a suitable amount of time, such as from afew minutes to 48 hours. The carbapenem C4 is obtained by conventionalisolation/purification methodology known in the art.

Generally speaking, the milder conditions of the synthesis shown in FlowSheet C allow for a wider range of functional groups R^(a) to be presentwhen attaching the naphthalene, than the synthesis illustrated in FlowSheet B. However, in certain cases it is advantageous for the R^(a)substituent(s) of the stannane C3 to be introduced in a protected orprecursory form. Final elaboration of R^(a) from a precursorsubstituent, e.g. hydroxymethyl, may be accomplished on carbapenemintermediate C4. Removal of protecting groups then provides the finalcompound of Formula I. Such final elaboration and deprotection isdescribed in further detail below. ##STR14##

Azetidin-2-one B2, a pyridyl-thioester, is a well known compound in theproduction of carbapenems. Diverse synthetic schemes useful to make B2may be imagined by the skilled artisan. Particularly useful to theinstant invention is a synthetic scheme set out further in Flow Sheet Dbelow in which the symbol R is as defined above. The steps for preparingintermediate B2 are analogous to the procedures described, for example,in U.S. Pat. Nos. 4,260,627 and 4,543,257; L.D. Cama et al. Tetrahedron,39, 2531 (1983); R. N. Guthikonda et al. J. Med. Chem., 30, 871 (1987).##STR15##

The steps for preparing the 2-oxocarbapenam intermediate C1 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Letters, 21, 2783 (1980), T. Salzmann et al., J. Am.Chem. Soc., 102, 6161 (1980), and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 108, 4675 (1986). The syntheses are alsodisclosed in U.S. Pat. No. 4,269,772, U.S. Pat. No. 4,350,631, U.S. Pat.No. 4,383,946 and U.S. Pat. No. 4,414,155 all assigned to Merck andCompany, Inc.

The general synthesis description depicted above in the Flow Sheetsshows a protected 1-hydroxyethyl substitution on the 6-position of thecarbapenem. After final deprotection, a 1-hydroxyethyl substituent isobtained, which is preferred in most cases. However, it has been beenfound that with certain 2-side-chain selections, the ultimate balance offavorable properties in the overall molecule may be enhanced byselection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23 (8), 1915 (1985); BE 900 718 A(Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanraku Ocean).

In the compounds of the present invention, one of the R^(a) substituentsmust be of Type I. As a general matter, it is conjectured thatanti-MSRA/MRCNS activity results from the configuration of the overallmolecule uniquely conferred by the naphthalene nucleus. The Type Isubstituent provides still greater anti-MRSA/MRCNS activity to themolecule.

The Type II substituents are distinguishable from Type I substituentschemically and with respect to the biological properties which theyconfer. In related compounds, it has been found that the Type IIsubstituted compounds afford greater water solubility and reducedpotential for CNS side effects. Substituents which tend to conferimproved water solubility on the overall compound have been founduseful, since they are contemplated to thereby improve the transport ofthe compound involved. Although a substantial number and range of TypeII substituents have been described herein, all of these arecontemplated to be a part of the present invention based on thebiological performance of substituents related in terms of theirmedicinal chemistry.

Since it is possible to combine, in the compounds of the presentinvention, the required Type I substituent with the optional Type IIsubstituents, there can be obtained a combination of desired attributesin the final overall molecule not attainable with a single substituent,i.e., improved anti-MRSA/MRCNS activity together with enhanced watersolubility.

All of the Type I substituents employed in the compounds of the presentinvention may have quaternary nitrogen groups, and these include bothcyclic and acyclic types, as is described under Type I hereinabove. Asalready pointed out above, it is required that one, but no more thanone, of the substituents R^(a) must be a member selected from the groupconsisting of the definitions under Type I. It is optional that one, orat most three, of the remaining substituents may be a member selectedfrom the group consisting of definitions under Type II. For example,R^(a) at position 7- may be a Type I substituent and R^(a) at position1- may be of Type II, while the remaining substituents are hydrogen.

In preferred compounds of Formula I, R¹ is hydrogen. More preferably, R¹is hydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--. In the mostpreferred case, R¹ is hydrogen and R² is (R)--CH₃ CH(OH)--. While R═H isusually preferred, there are instances in which R═CH₃ may provideimproved chemical stability, water solubility, or pharmacokineticbehavior. The substituent R═CH₃ may be of either configuration, i.e.,the α or β-stereoisomer. Additionally, in preferred compounds, at leastone R^(a) in the 1- or 7- position of the naphthalene is other thanhydrogen.

Preferred Type I. (a) substituents include: ##STR16## where X=O, S, orNR^(c). For structures of Type I. (a), where R^(c) is shown to have anindefinite position, it may be attached to any carbon of the ring.

Preferred Type I . (b) substituents include: ##STR17## where X=O, S, orNR^(c) and X'=O or S. For structures of Type I. (b), where R^(c) and/orA' are shown to have indefinite positions, they are independentlyattached to any carbon atom of the ring.

Preferred Type I. (c) substituents include: ##STR18## where W is O, S,NR^(e), N(O)R^(e), SO, SO₂ or N⁺ (R^(e))₂ and W' is N⁺ R^(e) or NO. Forstructures of Type I. (c), where R^(q) is shown to have an indefiniteposition, it may be attached to any carbon atom of the ring.

Preferred Type I. (d) substituents include: ##STR19## For structures ofType I. (d), where R^(q) and/or A'_(p) is shown to have an indefiniteposition, it may be attached to any carbon atom of the ring.

The R^(c) substituents herein are intended to represent suitable furthersubstituents on the Type I. (a) or (b) substituents for the naphthylring. As seen above, these Type I. (a) or (b) substituents aremonocyclic or bicyclic aromatic groups containing heteroatoms. Giventhis class of primary substituent, further suitable substituents may bereadily discovered in the carbapenem art. For example, suitablesubstituents for Type I. (a) or (b) substituents are generally taught inU.S. Pat. No. 4,729,993 assigned to Merck and Co. or in U.S. Pat. No.4,746,736 assigned to Bristol-Myers Co. These patents are herebyincorporated by reference.

Broadly, R^(c) may be the same or different and may be selected on anindependent basis from the group as defined above. While a single suchsubstitution is preferred, there is occasion to use up to two suchsubstituents on an R^(a), e.g., where it is desired to enhance theeffect of a particular substituent group by employing multiplesubstituents. The particular choice of R^(c) will depend upon thesituation. For instance, a specific R^(c) may lend particular stabilityto a nitrogen cation. At other times it may be desired to employ asubstituent known to enhance antibacterial activity of the overallmolecule against a particular bacterium, for example, while alsoemploying a substituent known to improve some other property such aswater solubility or the duration of action of the overall molecule.

The scope of R^(c) herein includes two specific types of furthersubstituent attached to the Type I. (a) or (b) substituent. A first typeof R^(c) are those attached to a ring carbon and a second type of R^(c)are those attached to a neutral ring nitrogen. Persons skilled in theart will readily recognize that a wide range of organic substituents aresuitably used as R^(c). Persons skilled in the art will also recognizethat some substituents including the --NR^(y) R^(z) substituents, usefulfor one purpose of R^(c), i.e. carbon substitution, are not equallyuseful in the other, i.e. nitrogen substitution.

Preferred R^(c) attached to ring carbon atoms are --NH₂, --SCH₃,--SOCH₃, --CH₂ OH, --(CH₂)₂ OH, --OCH₃, --COOM^(b), --CH₂ COOM^(b),--CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --SO₃ M^(b), --CH₂ SO₃M^(b), --CH₂ CH₂ SO₃ M^(b), --Br, --Cl, --F, --I, --CH₃, CH₂ CH₃, CH₂CONH₂ and CH₂ CON(C₁ -C₄ alkyl) where M^(b) is defined above. PreferredR^(c) attached to neutral ring nitrogen atoms are --CH₂ OH, --(CH₂)₂ OH,--CH₂ COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --CH₂ SO₃M^(b), --CH₂ CH₂ SO₃ M^(b), --CH₃, CH₂ CH₃, CH₂ CONH₂ and CH₂ CON(C₁ -C₄alkyl) where M^(b) is defined above.

It is preferred that each Type I. (a) or (b) substituent have no morethan two R^(c) substituents which are other than hydrogen. Thus, theformula shown above for Type I. (a) substituents has up to two R^(c)substituents with the remainder of course being hydrogen. Further, theformula for the Type I. (b) substituent also allows up to two R^(c). Inaccordance with these formulae, the previously listed more specificstructures should be interpreted to have no more than two R^(c) for eachmonocyclic or bicyclic group. Similarly for Type I. (c) or (d)substituents it is preferred that any monocylic or bicyclic group haveno more than single R^(q) substituent.

The scope of R^(d) includes a single Type of further substituentattached a Type I. (b) or (d) substituent. The R^(d) substituents areattached to a cationic nitrogen which may or may not be aromatic.Preferred R^(d) attached to cationic nitrogen atoms are hydrogen, --CH₃,CH₂ CH₃, --CH₂ CH₂ CH₃, --CH₂ COOM^(b), --CH₂ SO₃ M^(b), --NH₂ andO.sup.(-), where M^(b) is defined above.

The formulas depicting Type Ib, Ic, and Id substituents show positivelycharged states for those substituents. It is understood that certain ofthose substituents, which are cationic by virtue of having a protonatinghydrogen atom attached to the nitrogen, may also exist or be producedunder certain conditions as a neutral substituent by virtue of theabsence of such a hydrogen atom (ie. in Type Ib, when there is no R^(d); in Type Ic, when there is no R^(w) ; and in Type Id, when there iszero to one R^(d), depending on type of heterocycle). Whether such aType Ib, Ic, or Id substituent will be predominately cationic or neutralin a given physical state will be governed by principles of acid-basechemistry, which are well known to those skilled in the art. Forexample, the particular ratio of neutral form to cationic form willdepend upon the basicity of the amine and acidity of a solution. Whensuch a substituent is in a protonated quaternized state, the compoundexists as a zwitterion which is internally balanced as to charge or asan ammonium salt which is externally balanced. In illustration, if thereis no R^(d) on a Type Ib substituent, it is understood that such asubstituent is neutral (there is no positive charge on the nitrogen). Acompound containing such a substituent is typically produced in thisform as a salt, wherein M is an alkali metal, and may exist in solutionin its neutral form. However, depending upon conditions, a compoundcontaining a neutral Type Ib substituent may be in equilibrium with, andmay also be represented by a formula showing, the corresponding compoundcontaining the quaternized protonated substituent where R^(d) is presentand is a hydrogen atom. Furthermore the same compound may exist with theType Ib substituent in a completely protonated quaternized form, forinstance in an aqueous solution in the presence of a stoichiometricamount of a strong mineral acid. It is intended herein that both theprotonated (cationic) and the unprotonated (neutral) forms of Types Ib,Ic and Id substituents of the kinds just described are within the scopeof the present invention.

Suitable A spacer moieties include --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂--, --CH₂ CH₂ CH₂ CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --, --SO₂ CH₂ --,--SCH₂ CH₂ --, --SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂ CH₂ --,--N(CH₃)CH₂ CH₂ --, --CH₂ N(CH₃)CH₂ CH₂ --, --CONHCH₂ CH₂ --, --SO₂NHCH₂ CH₂ --, --COCH₂ --, --CH═CHCH₂ -- and --CH₂ OCH₂ CH₂ --.Preferably, where Q is O, S, NH or N(C₁₋₄ alkyl), then n is 2-6.

Suitable A' are listed for A above. Further A' may suitably be --O--,--S--, --NH--, --SO₂ --, --SO₂ NH--, --CONH--, --CH═CH--, --CH₂ S--,--CH₂ NH--, --CONHCH₂ -- or --SO₂ NHCH₂ --.

It is understood that the chemical formulas defining A and A' spacersare to be read in a normal left to right manner and are not to be readin any other direction. Thus (CH₂)_(m) --Q--(CH₂)_(n) is not equivalentto, and should not be read as, (CH₂)_(n) --Q--(CH₂)_(m).

The Type I. cationic substituents are generally added to the naphthalenefollowing attachment of the naphthalene to the carbapenem. Conveniently,the naphthalene side-chain should be synthesized with a precusorsubstituent which may be elaborated into the desired cationicsubstituent. The identity of the precursor substituent will varyaccording to the particular R^(a) desired. For example, one suchprecursor substituent is --A--OH, such as hydroxymethyl.

The hydroxymethyl precursor substituent may be elaborated into cationicsubstituents of Type I.(a) by converting the hydroxyl into an activeleaving group such as an iodide (giving --A--I) followed by reactionwith a desired nitrogen containing aromatic compound. More particularly,two alternative procedures may be utilized to produce a leaving group onthe moiety --A-- and subsequently to replace such a leaving group withcationic substituents of the type just described.

For a first procedure, the hydroxyl group of --A--OH may be converted toa methanesulfonate group by treating with methanesulfonyl chloride inthe presence of triethylamine. A suitable solvent, e.g.,dichloromethane, is employed and the reaction is carried out at reducedtemperatures. In turn, the methanesulfonate intermediate may convertedto the reactive iodide derivative by treatment with sodium iodide in asuitable solvent, e.g., acetone, at reduced or ambient temperatures.Alternatively, the hydroxyl group may be directly converted into theiodide group by common methods known to the art. For example, treatmentof the hydroxyl group with methyl triphenoxyphosphonium iodide in asuitable solvent, such as dimethylformamide, at reduced or ambienttemperatures, directly provides the desired iodide. Once the iodide hasbeen formed, the introduction of the cationic substituent isaccomplished simply by treating the iodide with the desired nitrogencontaining compound, e.g. a heteroaromatic compound such as pyridine.The reaction will proceed in a suitable solvent, such as acetonitrile,at or about room temperature. This displacement reaction may also befacilitated by the addition of excess silver trifluoromethanesulfonateto the reaction mixture, in which case reduced temperatures are oftendesireable.

For a second procedure, the hydroxyl group of --A--OH may be convertedinto the reactive trifluoromethanesulfonate (triflate) group. However,such an activating group cannot be isolated by conventional techniquesbut may be formed and used in situ. Thus, treatment of the hydroxylgroup with trifluoromethanesulfonic (trific) anhydride in the presenceof a hindered, non-nucleophilic base such as 2,6-lutidine,2,4,6-collidine, or 2,6-di-tert-butyl-4-methylpyridine in a suitablesolvent, such as dichloromethane, at reduced temperatures provides forthe generation of the triflate activating group. Introduction of thecationic group is then accomplished by reacting the above triflate insitu with the desired nitrogen containing compound at reducedtemperature. In certain cases it is possible and desirable to use thereacting nitrogen containing compound as the base for the formation ofthe triflate activating group. In this case treatment of the hydroxylgroup with triflic anhydride in the presence of at least two equivalentsof the reacting nitrogen compound under the conditions described aboveprovides the cationic substituent.

Where the cationic substitution has a substituent R^(c), the most facilemethod of providing such a substituent is to employ as the reactant inthe preparation methods described above a nitrogen containing compoundwhich already has the desired substituent. Such substituted compoundsare readily available starting materials or may be prepared in astraight-forward manner using known literature methods.

The Type I.(b) cationic substituents are prepared by quaternization ofan aromatic ring nitrogen of a neutral precursor substituent on thenaphthalene ring. Examples of neutral precursor substituents are--CONHCH₂ --(2-pyridyl), --CONHCH₂ --(4-pyridyl) or --SO₂ CH₂--(4-pyridyl). Quaternization is accomplished by reacting the nitrogencompound in an inert organic solvent (e.g. CH₂ Cl₂) at about 0° C. toroom temperature with an alkylating agent R^(d) --Y where R^(d) is givenabove and Y is a leaving group such as iodide, bromide, mesylate(methanesulfonate), tosylate (p-toluenesulfonate) or triflate.Alternatively, the aromatic ring nitrogen may be quaternized by reactionwith an oxidizing agent such as 3-chloroperbenzoic acid (giving theN-oxide) or an amidinating reagent such aso-(2,4,6-triisopropylbenzenesulfonyl)hydroxylamine (giving the N-aminoderivative) in a suitable solvent (e.g. dichloromethane or CH₃ CN) atabout room temperature. In addition, the neutral precursor substituentmay be rendered cationic through protonation of the basic aromatic ringnitrogen. This may be accomplished by treatment of the neutral precursorwith a suitable inorganic or organic acid, e.g. hydrochloric acid,phosphoric acid, hydrobromic acid, acetic acid or benzoic acid.Protonation may further be accomplished by a carboxylic acid functionelsewhere in the molecule, including the C-3 carboxyl on the carbapenem.The neutral precursor substituent may be already attached to thenaphthalene ring at the time of its connection to the carbapenem, or itmay be elaborated from a simpler precursor after connection to thecarbapenem. An example of a precursor substituent for elaboration is--A'--OH such as hydroxymethyl. In one suggested synthesis, the hydroxylmay be converted to a reactive leaving group such as iodo as describedabove. The iodide is then reacted in a nucleophilic displacementreaction with a nitrogen containing aromatic compound which has anucleophilic side-chain substituent such as CH₂ SH or CH₂ NH₂. In thisdisplacement reaction, it is the side-chain substituent that is thereacting nucleophile and not the aromatic ring nitrogen. Suitablesubstrates for this reaction include 2-(mercaptomethyl)pyridine,2-aminopyridine, 2-(aminomethyl)pyridine or 4-(mercaptomethyl)pyridine.The reaction is carried-out in an inert organic solvent, e.g. methylenechloride, at from about 0° C. to room temperature in the presence of anon-nucleophilic base such as triethylamine or diisopropylethylamine.Quaternization or protonation as described above then gives the TypeI.(b) cationic substituent. A second suggested synthesis of a Type I.(b)cationic substituent starting from a precursor --A'--OH (e.g.hydroxymethyl) consists of oxidation of the alcohol functionallity to analdehyde followed by Wittig-type olefination with an appropriatenitrogen-containing aromatic substituted reagent, and finallyquaternization. The oxidation may be conveniently accomplished by aSwern oxidation employing oxalyl chloride-dimethylsulfoxide followed bytriethylamine. The reaction is conducted in methylene chloride as asolvent at from -70° C. to 0° C. The Wittig reaction is carried-out byreacting the aldehyde with the desired Wittig reagent in a polar solventsuch as acetonitrile or dimethylsulfoxide at about room temperature.Suitable Wittig reagents include: pyridylmethylenetriphenylphosphorane,quinolylmethylenetriphenylphosphorane andthiazolylmethylenetriphenylphosphorane. Quaternization or protonation asdescribed above then completes the synthesis of the Type I.(b) cationicsubstituent. Depending on the particular R^(a) of Type I.(b) that isdesired, many other synthesis schemes may be employed, as would beapparent to an organic chemist skilled in the art.

The Type I.(c) cationic substituent may be prepared in an analogousmanner to that described for I.a) substituents except that the nitrogencontaining compound employed in the displacement reaction is analiphatic amine (i.e. NR^(y) R^(z) R^(w)). However, in cases where theamino group is directly bonded to the naphthalene nucleus (i.e. --A_(p)N⁺ R^(y) R^(z) R^(w) where p=0) the amine is most conveniently attachedto the naphthalene prior to its incorporation into the carbapenemsystem. If such an amine is primary or secondary, it may requireprotection with a suitable amine protecting group during the stepsemployed to attached the naphthalene to the carbapenem. Tertiary aminesrequire no protection and may be quaternized or protonated as describedfor the Type I.(b) cationic substituents.

The Type I.(d) cationic substituents are prepared by quaternization orprotonation of a non-aromatic ring nitrogen of an appropriate neutralprecursor substituent on the naphthalene ring. Quaternization orprotonation is accomplished as described above for the Type I.(b)substituents. As with the Type I.(b) substituents, the neutral precursormay already be attached to the naphthalene ring at the time of itsconnection to the carbapenem, or the neutral precursor may be elaboratedfrom a simpler precursor substituent on the naphthalene ring after itsconnection to the carbapenem. Examples of neutral precursor substituentsare: --CONH(3-quinuclidinyl), --CONH[4-(N-methylpiperidinyl)], --SO₂ CH₂CH₂ [2-(N-methylpyrrolidinyl)], --SO₂ [1-(4-methylpiperazinyl)] and--CH₂ [1-(4-methylpiperazinyl)]. Elaboration of the neutral precursorsubstituent from a simpler substituent such as hydroxymethyl may beaccomplished in an analogous manner to that described previously for theType I.(b) substituents by employing appropriate reagents to introducethe Type I.(d) non-aromatic ring nitrogen moiety which is subsequentlyto be quaternized or protonated.

Among preferred R^(a) of Type II are C₁₋₄ alkyl mono-substituted withhydroxy, such as, hydroxymethyl; formyl; carboxy, such as, --COOK;carbamoyl, such as, --CONH₂ ; hydroximinomethyl, such as, --CH═NOH orcyano.

In regard to this preferred substitution, the hydroxymethyl may beobtained in any of the positions 1, 5, 6, 7 or 8 of the naphthalene ringby employing the appropriately substituted starting material (ie. A1 inFlow Sheet A). Thus, proceeding as shown in Flow Sheets A and B, butstarting with an "isomeric" A1, a corresponding "isomeric" B3A and acorresponding "isomeric" B4 may be produced.

The preferred formyl substitution on the naphthalene may be obtainedfrom the hydroxymethyl substitution of B4 or isomeric B4 just describedby a Swern oxidation. For example, isomeric B4 is oxidized in methylenechloride at from -70° C. to room temperature employing oxalylchloride-dimethyl sulfoxide, followed by triethylamine, as the activeagent. Alternatively, this oxidation may be conveniently accomplishedusing N-methylmorpholine-N-oxide and a catalytic amount oftetra-n-propyl-ammonium peruthenate in methylene chloride. Obviously,the position of the resultant formyl substitution will depend upon theposition of the hydroxymethyl substitution in isomeric B4.

The preferred --CH═NOH substitution on the naphthalene may beconveniently obtained from the formyl substitution just described. Thisis accomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the naphthalene may be obtained fromthe --CH═NOH substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The preferred --COOK substitution on the naphthalene may be obtainedfrom the hydroxymethyl substituted B3A or isomeric B3A described above.For example, an isomeric B3A is oxidized with Jones reagent to convertthe hydroxymethyl substituent into a carboxylic acid group. Theoxidation with Jones reagent may be incompatible with the carbapenem andthus is optimally performed before ring closure. Prior to ring closure,the carboxy is protected as its allyl ester to permit cyclization of thecarbapenem. Protection is carried out by alkylating with allyl bromideand triethylamine. Deprotection following cyclization is carried outwith palladium catalyzed deallylation in a solution containing potassium2-ethylhexanoate as described in McCombie and Jeffrey, J. Org. Chem.,47, 2505 (1983). Deprotection in such a solution yields the desiredpotassium salt.

The preferred carbamoyl substitution on the naphthalene may be obtainedfrom B3A or "isomeric" B3A by oxidizing the hydroxymethyl with Jonesreagent to the corresponding carboxylic acid as described above. Thiscarboxy is converted to --CONH₂ by sequentially contacting with1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and ammonia in an organic solvent at roomtemperature. Alternatively, the carboxy may be reacted with1,1'-carbonyldiimidazole in an aprotic polar solvent, such astetrahydrofuran followed by treatment with aqueous ammonia to give thesame --CONH₂. Substituted amides may of course be obtained by replacingammonia with the corresponding substituted amine. In contrast to thecarboxy substitution, this carbamoyl group requires no protection forthe conditions of carbapenem cyclization.

Compounds substituted with the preferred R^(a) of Type II just describedmay also be obtained by employing the synthesis shown in Flow Sheet C.In this case, the synthetic transformations just described may becarried-out on intermediate C3 prior to attachment of the naphthyl sidechain to the carbapenem or on C4 after such attachment.

In addition to or including the above, suitable R^(a) of Type IIinclude:

    ______________________________________                                        --OCH.sub.3        --OCH.sub.2 CO.sub.2 Na                                    --OCH.sub.2 CH.sub.2 OH                                                                          --CF.sub.3                                                 --F                --Cl                                                       --Br               --I                                                        --OH               --OCOCH.sub.3                                              --OCONH.sub.2      --SCH.sub.3                                                --SOCH.sub.3       --SO.sub.2 CH.sub.3                                        --SCH.sub.2 CH.sub.2 OH                                                                          --SOCH.sub.2 CH.sub.2 OH                                   --SO.sub.2 NH.sub.2                                                                              --SO.sub.2 N(CH.sub.3).sub.2                               --NHCHO            --NHCOCH.sub.3                                             --NHCO.sub.2 CH.sub.3                                                                            --NHSO.sub.2 CH.sub.3                                      --CN               --CHO                                                      --COCH.sub.3       --COCH.sub.2 OH                                            --CH═NOH       --CH═NOCH.sub.3                                        --CH═NOCH.sub.2 CO.sub.2 H                                                                   --CH═NOCMe.sub.2 CO.sub.2 H                            --CH═NOCMe.sub.2 CO.sub.2 Me                                                                 --CO.sub.2 CH.sub.2 CH.sub.2 OH                            --CONH.sub.2       --CONHCH.sub.3                                             --CON(CH.sub.3).sub.2                                                                            --CONHCH.sub.2 CN                                          --CONHCH.sub.2 CONH.sub.2                                                                        --CONHCH.sub.2 CO.sub.2 H                                  --CONHOH           --CONHOCH.sub.3                                            tetrazolyl         --CO.sub.2 Na                                              --SCF.sub.3        --PO.sub.3 NaH                                             --CONHSO.sub.2 Ph  --CONHSO.sub.2 NH.sub.2                                    --SO.sub.3 Na      --SO.sub.2 NHCN                                            --SO.sub.2 NHCONH.sub.2                                                                          --CH═CHCN                                              --CH═CHCONH.sub.2                                                                            --CH═CHCO.sub.2 Na                                     --C.tbd.C--CONH.sub.2                                                                            --C.tbd.C--CN                                              --CH.sub.2 OH      --CH.sub.2 N.sub.3                                         --CH.sub.2 CO.sub.2 Na                                                                           --SO.sub.2 CH.sub.2 CH.sub.2 OH and                                           --CH.sub.2 I.                                              ______________________________________                                    

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the final product is prepared.Deblocking may be carried out in a conventional manner. For compoundsprepared according to Flow Sheet B, deprotection may be carried out in apalladium catalyzed reaction in a solution containing potassium2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively, anothersuitable nucleophile such as pyrrolidine. Alternatively, for thoseprepared via Flow Sheet C, deprotection is conducted sequentially. Thus,compound C4 is exposed initially to aqueous acidic conditions aceticacid or dilute HCl or the like, in an organic solvent such astetrahydrofuran at 0° C. to ambient temperature for from a few minutesto several hours. The resulting desilylated carbapenem may be isolatedby conventional techniques, but is more conventiently taken into thefinal deprotection process. Thus, addition of an inorganic base such asNaHCO₃ or KHCO₃ and 10% Pd/C followed by hydrogenation provides for theremoval of the p-nitrobenzyl protecting group and the formation of thefinal compound of Formula I.

The overall molecule must be electronically balanced. Since a quaternarynitrogen is present in the compounds of the present invention, abalancing anion must also, in that case, be present. This is usuallyaccomplished by allowing COOM to be COO⁻. However, where M is, e.g., apharmaceutically acceptable ester, a counterion (anion) Z⁻ must beprovided, or alternatively, an anionic substituent might be utilized. Acounterion must also be provided or additional anionic substituentutilized where there is more than one quaternary nitrogen. Further, itis within the scope of this invention to utilize an anionic substituentwhere the quaternary nitrogen is already balanced by COOM═COO⁻. In thatcase, it will be understood that it is necessary to provide a counterion(cation) for the anionic substituent. However, it is well within theskill of a medicinal chemist, to whom there is available many suitableanionic and cationic counterions, to make such choices.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "quaternary nitrogen" as used herein refers to a tetravalentcationic nitrogen atom including the cationic nitrogen atom in atetra-alkylammonium group (eg. tetramethylammonium, N-methylpyridinium),the cationic nitrogen atom in a protonated ammonium species (eg.trimethylhydroammonium, N-hydropyridinium), the cationic nitrogen atomin an amine N-oxide (eg. N-methylmorpholine-N-oxide, pyridine-N-oxide),and the cationic nitrogen atom in an N-amino-ammonium group (eg.N-aminopyridinium).

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(x)group, to have a specific and limited meaning, being only monocyclic.While the Type I. (a) and (b) substituents also clearly includeheteroaryl groups, being both monocyclic and bicyclic, the term"heteroaryl" has not been used in association with the definitions ofthose substituents above. It is required that the monocyclic heteroarylhave at least one nitrogen atom, and optionally at most only oneadditional oxygen or sulfur heteroatom may be present. Heteroaryls ofthis type are pyrrole and pyridine (one N); and oxazole, thiazole oroxazine (one N plus one O or one S). While additional nitrogen atoms maybe present together with the first nitrogen and oxygen or sulfur,giving, e.g., a thiadiazole (two N's plus one S), the preferredheteroaryls are those where only nitrogen heteroatoms are present whenthere is more than one. Typical of these are pyrazole, imidazole,pyrimidine and pyrazine (two N's) and triazine (three N's).

The heteroaryl group of R^(x) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstitutent choices may not be appropriate.

Listed in Table I are specific compounds of the instant invention:

                  TABLE I                                                         ______________________________________                                         ##STR20##                                                                    ______________________________________                                        M       R.sup.a              R.sup.a Position                                 ______________________________________                                        (-)                                                                                    ##STR21##           1                                                (-)                                                                                    ##STR22##           5                                                (-)                                                                                    ##STR23##           6                                                (-)                                                                                    ##STR24##           7                                                (-)                                                                                    ##STR25##           8                                                (-)                                                                                    ##STR26##           1                                                (-)                                                                                    ##STR27##           5                                                (-)                                                                                    ##STR28##           6                                                (-)                                                                                    ##STR29##           7                                                (-)                                                                                    ##STR30##           8                                                (-)                                                                                    ##STR31##           1                                                (-)                                                                                    ##STR32##           5                                                (-)                                                                                    ##STR33##           6                                                (-)                                                                                    ##STR34##           7                                                (-)                                                                                    ##STR35##           8                                                (-)                                                                                    ##STR36##           7                                                (-)                                                                                    ##STR37##           7                                                (-)                                                                                    ##STR38##           7                                                (-)                                                                                    ##STR39##           7                                                (-)                                                                                    ##STR40##           7                                                         ##STR41##           7                                                K                                                                                      ##STR42##           7                                                K                                                                                      ##STR43##           7                                                K                                                                                      ##STR44##           7                                                (-)                                                                                    ##STR45##           6                                                (-)                                                                                    ##STR46##           7                                                (-)                                                                                    ##STR47##           7                                                (-)                                                                                    ##STR48##           7                                                (-)                                                                                    ##STR49##           7                                                (-)                                                                                    ##STR50##           7                                                (-)                                                                                    ##STR51##           1                                                (-)                                                                                    ##STR52##           1                                                (-)                                                                                    ##STR53##           7                                                (-)                                                                                    ##STR54##           1                                                (-)                                                                                    ##STR55##           7                                                (- )                                                                                   ##STR56##           1                                                (-)                                                                                    ##STR57##           1                                                (-)                                                                                    ##STR58##           7                                                (-)                                                                                    ##STR59##           7                                                (-)                                                                                    ##STR60##           7                                                (-)                                                                                    ##STR61##           7                                                (-)                                                                                    ##STR62##           1                                                (-)                                                          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       7                                                (-)                                                                                    ##STR83##           7                                                (-)                                                                                    ##STR84##           1                                                ______________________________________                                                         R.sup.a               R.sup.a'                                                Posi-                 Posi-                                  M    R.sup.a     tion   R.sup.a'       tion                                   ______________________________________                                        (-)  CN          1                                                                                     ##STR85##     7                                      (-)  SOCH.sub.3  1                                                                                     ##STR86##     7                                      (-)  CO.sub.2 K  1                                                                                     ##STR87##     7                                      (-)  CO.sub.2 K  1                                                                                     ##STR88##     7                                      (-)                                                                                 ##STR89##  1                                                                                     ##STR90##     7                                      (-)                                                                                 ##STR91##  1                                                                                     ##STR92##     7                                      (-)  SO.sub.3 K  1                                                                                     ##STR93##     7                                      (-)  CO.sub.2 K  1                                                                                     ##STR94##     7                                      (-)  SO.sub.3 K  1                                                                                     ##STR95##     6                                      (-)  SO.sub.3 K  5                                                                                     ##STR96##     7                                      (-)  CHO         1                                                                                     ##STR97##     7                                      ______________________________________                                    

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above may also includenon-toxic acid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

The pharmaceutical acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogentation. Examples of such esterprotecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl,allyl, benzyl, trichloroethyl, silyl such as trimethylsilyl,trimethylsilylethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl,p-methoxyphenyl, 4-pyridylmethyl, and t-butyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of a DHP inhibitor. However, such use isoptional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenem antibacterial agents aredisclosed in the prior art [see European Patent Applications No.79102616.4 filed July 24, 1979 (Patent No. 0 007 614); and No.82107174.3, filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications (1) define the procedure for determining DHP susceptibilityof the present carbapenems and (2) disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. All temperaturesare in degrees Celsius.

EXAMPLE 1 ##STR98## 3-Bromo-1-(hydroxymethyl)napthalene (1)

To a stirred solution of 1.0 g (3.98 mmoles) of 3-bromo-1-naphthoic acidin 38 ml of anhydrous diethyl ether was added dropwise a 0.86 M lithiumaluminum hydride in diethyl ether solution (44 ml, 3.78 mmoles). Theresulting slurry was stirred at reflux under a N₂ atmosphere for 3hours. The slurry was cooled to rt and moist Na₂ SO₄ was added. Theresulting slurry was filtered through a MgSO₄ plug and the filtrateconcentrated under vacuum to provide 782.7 mg of white residue.Purification on silica gel plates which were eluted with CH₂ Cl₂ gave722.3 mg of 3-bromo-1-(hydroxymethyl)naphthalene as a white crystallinesolid.

¹ H-NMR (300 MHz, CDCl₃): δ 1.79 (bs, CH₂ OH), 5.15 (s, CH₂ OH), 7.54(m, naphthyl-H6 and H7), 7.66 (s, naphthyl-H2), 7.79 (m, naphthyl-H5),7.97 (s, naphthyl-H4), 8.03 ppm (m,naphthyl-H8). IR (CH₂ Cl₂): 3605cm⁻¹.

EXAMPLE 2 ##STR99## 3-Bromo-1-(t-butyldimethylsilyloxymethyl)naphthalene (2)

To a solution of 1.49 g (6.3 mmoles) of3-bromo-1-(hydroxymethyl)-naphthalene in 25 ml anhydrous CH₂ Cl₂ wereadded sequentially N,N-dimethyl-4-aminopyridine (76.8 mg, 0.63 mmoles),t-butyldimethylchlorosilane (1.23 g, 8.2 mmoles) and triethylamine (1.22ml, 8.8 mmoles). The resulting solution was stirred at room temperaturefor 2 hours under a N₂ atmosphere and then partitioned between EtOAc andice/H₂ O. The organic phase was separated, washed with brine, dried withanhydrous Na₂ SO₄, filtered and concentrated under vacuum to provide apale yellow liquid. The crude reaction residue was purified by columnchromatography (44 g silica gel, packed and eluted with 9:1 hexanes:CH₂Cl₂) to provide 2.19 g of the title compound as a clear liquid.

¹ H-NMR (200 MHz, CDCl₃): δ 0.15 (s, CH₃ Si), 0.97 (s,(CH₃)₃ CSi), 5.17(s,CH₂ O), 7.22-7.95 ppm (m, ArH).

EXAMPLE 3 ##STR100##(3S,4R)-1-(Allyloxycarbonyl-triphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[1-(t-butyldimethylsilyloxymethyl)-3-naphthylcarbonyl]methyl-azetidin-2-one(4)

To a mixture of magnesium turnings (160 mg, 6.6 mmoles) in 15 mlanhydrous THF was added the bromo-naphthalene 2 prepared in the previousexample (2.09 g, 6.0 mmoles). The stirring was stopped and 35 μl of1,2-dibromoethane was added close to the magnesium surface. Heat wasapplied to initiate the reaction and the mixture then stirred at 30°under a N₂ atmosphere for 2.5 hours. At the end of this time the heatwas removed and the yellow Grignard solution was employed as describedbelow.

To a solution of 2.11 g (3.0 mmoles)of(3S,4R)-1-(allyloxycarbonyltriphenylphosphorylidene)methyl-3-[(R)-1-(allyloxycarbonyloxy)ethyl)-4-[(2-pyridylthio)carbonyl]methyl-azetidin-2-one,3, in 20 ml anhydrous tetrahydrofuran at -9° under a N₂ atmosphere wasadded 11.5 ml (ca. 4.6 mmoles) of the above Grignard solution. Thereaction solution was stirred at -9° under a N₂ atmosphere for 50minutes and then 10 ml of saturated aqueous ammonium chloride solutionwas added. The resulting mixture was partitioned between EtOAc andice/H₂ O. The organic phase was separated and washed twice with ice/5Naqueous NaOH solution. The organic phase was then washed with brine,dried with anhydrous Na₂ SO₄, filtered and concentrated under vacuum toprovide 3.09 g of a yellow foam. The crude reaction residue was purifiedby column chromatography (150 g silica gel; packed and eluted with 3:2;hexanes: EtOAc) to provide 2.24 g of the title compound as a pale yellowfoam. IR (CH₂ Cl₂): 1745, 1680, 1615 cm⁻¹ ; 300 MHz

¹ H-NMR (CDCl₃): inter alia δ 0.15 (s, CH₃ Si), 0.96 (s, (CH₃)₃ CSi),1.18 (d, J=6.9 Hz, CH₃ CHCH), 5.18 ppm (s, naphthyl-CH₂).

EXAMPLE 4 ##STR101##(3S,4R)-1-(allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[1-(hydroxymethyl)-3-naphthylcarbonyl]methyl-azetidin-2-one(5)

To a solution of 2.9 g (3.32 mmoles) of azetidinone 4 in 35 ml anhydrousMeOH at 0° under a N₂ atmosphere was added a 0.75M methanolic sulfuricacid solution (6.64 ml, 4.98 mmoles). The resulting solution was stirred1.5 hrs. at 0° and then was concentrated under vacuum to 15 ml volume.The solution was then partitioned between EtOAc and ice/H₂ O/saturatedaqueous bicarbonate. The organic phase was separated and washed withbrine, dried with anhydrous Na₂ SO₄, filtered and concentrated undervacuum to provide 2.50 g of the title compound as a yellow foam.

¹ H-NMR (300 MHz, CDCl₃): inter alia δ 1.17 ppm (d, J=6.8 Hz, CH₃ CHCH).

IR (CH₂ Cl₂): 3600, 1745, 1680, 1620 cm⁻¹.

EXAMPLE 5 ##STR102##Allyl-(5R,6S)-2-(1-hydroxymethyl-3-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(6)

To solution of 2.5 g (3.3 mmoles) of azetidinone 5 in 300 ml anhydrousxylenes at room temperature under an argon atmosphere was added severalcrystals of hydroquinone. The solution was stirred 2 hours at 155° underan argon atmosphere and then cooled to room temperature. The solutionwas concentrated under vaccum to a yellow paste and the crude productpurified by column chromatography (45 g silica gel; packed and elutedwith 3:2; hexanes:EtOAc) to provide 1.28 g of the title compound.

¹ H-NMR (300 Mz, CDCl₃): δ 1.49 (d, J=5.8 Hz, CH₃ CH), 1.96 (t, CH₂ OH),3.3 (dd, J=10.0, 18.1 Hz, CHCH₂ C), 3.42 (m, CHCH₂ C and CHCHC═O) 4.31(dt, J=4.4, 7.8 Hz, CHCHCH₂), 4.67 (m, CH₃ CHCH and CH₂ CH═CH₂), 5.12(d, J=5.4 Hz, CH₂ OH), 5.29 (m, CH₂ CH═CH₂), 5.90 (m, CH₂ CH═CH₂), 7.54(m, naphthyl-H2, H6, H7) 7.78 (s, naphthyl-H4), 7.84 (dd, J=1.7, 8.4 Hz,naphthyl-H5), 8.05 ppm (d, J=8.6 Hz, naphthyl-H8);

IR (CH₂ Cl₂): 1780, 1745, 1720 cm⁻¹ ;

UV(dioxane): λ_(max) =288, 325 nm.

EXAMPLE 6 ##STR103##Allyl-(5R,6S)-2-(1-hydroxymethyl-6-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(7)

In an analogous manner to that described in Examples 1-5, but startingwith 6-bromo-1-naphthoic acid [M. J. S. Dewar and P. J. Grisdale, J.Amer. Chem. Soc. 84, 3541 (1962)], the title compound was obtained as apale yellow foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.47 (d, J=6.35 Hz, 3H, CH₃), 3.25 (dd,J=9.8, 18.1 Hz, 1H, H1a), 3.37 (dd, J=9.0, 18.1 Hz, 1H, H1b), 3.42 (dd,J=8.2, 2.8 Hz, 1H, H5), 4.28 (dt, J=2.8, 9.4 Hz, 1H, H6), 4.55-4.75 (m,4H, --OCH₂ C═C), 5.08 (bs, 2H, ArCH₂ O), 5.1-5.4 (m, 5H, H8, --C═CH₂),5.75-6.0 (m, 2H, --CH═C), 7.4-7.55 (m, 3H, ArH), 7.79 (d, J=10.9 Hz, 1H,ArH), 7.83 (s, 1H, ArH), 8.04 ppm (d, J=8.79, 1H, ArH),

IR (CHCl₃): 3610 (OH), 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹(ester).

FAB-MS: m/e=478 (M+H).

EXAMPLE 7 ##STR104##Allyl-(5R,6S)-2-(2-hydroxymethyl-6-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(8)

In analogous manner to that described in Examples 1-5, but starting with6-bromo-2-naphthoic acid [L. G. Anderson and D. Johnston, J. Amer. Chem.Soc. 65, 239 (1943)], the title compound was obtained as a white foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.50 (d, J=6.77 Hz, 3H, CH₃), 3.25-3.55 (m,2H, H1), 3.45 (dd, J=13.2, 2.7 Hz, 1H, H6), 4.32 (dt, J=2.7, 9.5 Hz, 1H,H5), 4.55-475 (m, 4H, --OCH₂ C═C), 4.86 (d, J=5.37, 2H, ArCH₂ O),5.1-5.4 (m, 5H, H8, --C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 7.4-7.5 (m, 2H,ArH), 7.7-7.85 ppm (m, 4H, ArH).

IR (CHCl₃): 3600 (OH), 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹(ester).

FAB-MS: m/e=478 (M+H).

EXAMPLE 8 ##STR105##Allyl-(5R,6S)-2-(2-hydroxymethyl-7-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(9)

In a analogous manner to that described in Examples 1-5, but startingwith 7-bromo-2-naphthoic acid [W. Adcock and P. R. Wells, Aust. J. Chem.18, 1351 (1965)], the title compound was obtained as a pale yellow foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.49 (d, J=6.35 Hz, 3H, CH₃), 3.28 (dd,J=9.9, 18.1 Hz, 1H, Hla), 3.39 (dd, J=8.9, 18.1 Hz, 1H, Hlb), 3.44 (dd,J=8.4, 2.8 Hz, 1H, H6), 4.32 (dt, J=2.8, 9.3 Hz, 1H, H5), 4.55-4.75 (m,4H, --OCH₂ C═C), 4.85 (d, J=5.62 Hz, 2H, ArCH₂ O), 5.1-5.4 (m, 5H, H8,--C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 7.4-7.55 (m, 2H, ArH), 7.75-7.85 ppm(m, 4H, ArH).

IR(CHCl₃): 3600 (OH), 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹(ester).

EXAMPLE 9 ##STR106## Allyl-(5R,6S)-2-(1-hydroxymethyl-7-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(10)

In analogous manner to that described in Examples 1-5, but starting with7-bromo-1-naphthoic acid [H. Goldstein and H. A. Fisher, Helv. Chim.Acta 21, 1519 (1938)], the title compound was obtained as a white foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.51 (d, J=6.35 Hz, 3H, CH₃), 3.3-3.5 (m,2H, H1), 3.45 (dd, J=9.1, 2.8 Hz, 1H, H6), 4.33 (dt, J=2.8, 9.9 Hz, 1H,H5), 4.55-4.75 (m, 4H, --OCH₂ C═C), 5.1 (d, J=6.25 Hz, 2H, ArCH₂ O),5.1-5.4 (m, 5H, H8, --C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 7.4-7.55 (m, 3H,ArH), 7.75-7.85 (m, 2H, ArH), 8.20 ppm (s, 1H, ArH).

IR (CHCl₃): 3610 (OH), 1780 (β-lactam), 1745 (carbonate) 1725 cm⁻¹(ester).

FAB-MS: m/e=478 (M+H).

EXAMPLE 10 ##STR107## 2-Trimethylstannyl-6-hydroxymethylnaphthalene (12)

Bromonaphthalene 11 (1.72 g, 4.9 mmol), prepared in analogous manner tothat described in Examples 1 and 2, but starting with6-bromo-2-naphthoic acid, was dissolved in anhydrous THF (30 mL) andcooled to -78° C. under nitrogen. To this stirred solution was added a1.7M solution of t-BuLi in pentane (2.2 equiv.; 10.8 mmol; 6.3 mL).After 2.5 hours at -78° C., Me₃ SnCl (1.2 equiv.; 5.88 mmol; 1.17 g) wasadded as a solid. The cold bath was removed and the reaction allowed toreach ambient temperature. After 4 hours, the reaction was quenched withwater. The solvent was removed in vacuo and the residual dissolved inEt₂ O. Washing with water and brine was followed by drying over MgSO₄,filtering and removal of solvent. The residual was dissolved inanhydrous THF and treated with a 1.0 M solution of nBu₄ NF in THF (1.1equiv.; 5.4 mmol; 5.4 mL) at ambient temperature for 5 minutes.Quenching the reaction with saturated NH₄ Cl was followed by removal ofthe solvent in vacuo. The residual was dissolved in EtOAc and washedwith water and brine, dried with magnesium sulfate, filtered and thesolvent removed in vacuo. Purification by flash chromatography (30%EtOAc in hexanes) and crystallization from Et₂ O/hexanes at 0° provided1.38 g (87%) of stannyl alcohol as a white solid.

¹ H-NMR (300 MHz, CDCl₃): δ 0.34 (s, 9H), 1,69 (t, J=5.5 Hz, 1H), 4.85(d, J=6.0 Hz, 2H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H),7.75-7.81 (m, 3H), 7.94 ppm (s, 1H).

EXAMPLE 11 ##STR108## p-Nitrobenzyl-(5R,6S)-2-(2-hydroxymethyl-6-naphthyl)-6-[1R-(trimethylsilyloxy)ethyl]-carbapen-2-em-3-carboxylate(14)

A dry 15 mL receiving flask was charged with the bicyclic β-ketoester 13(143 mg; 0.41 mmol) and a magnetic stir bar and the system was purgedwith nitrogen. Two mL of anhydrous tetrahydrofuran (THF) was added andupon dissolution of 13, the reaction vessel was cooled to -78° C. underN₂. Diisopropylamine (0.063 mL, 0.45 mmol) was then added and thestirring was continued for 10 minutes. Trifluoromethanesulfonicanhydride (0.075 mL, 0.45 mmol) was added, followed by stirring foradditional 15 minutes. Triethylamine (0.062 mL. 0.45 mmol) was thenadded, followed by trimethylsilyl trifluoromethanesulfonate (0.087 mL,0.45 mmol).

While the above reaction was stirred for 20 minutes, the organostannane12 (144 mg, 0.45 mmol), tris(dibenzylideneacetone)dipalladium-chloroform(8.5 mg, 0.0082 mmol) and tris(2,4,6-trimethoxyphenyl)phosphine (17.4mg, 0.033 mmol) were weighed into a single vial and the vial was purgedwith nitrogen. When the above reaction time had elapsed,N-methylpyrrolidinone (2 mL) was added to the initial reaction mixturefollowed by the previously weighed solids. A 0.87M zinc chloride inether solution (0.52 mL, 0.45 mmol) was then added. The low temperaturebath was then removed and the reaction vessel was placed in a luke warmwater bath to allow it to quickly reach ambient temperature. Afterreaching ambient temperature, the mixture was stirred for 15 minutes.The reaction was then quenched by pouring the contents of the flask intoa 125 mL separatory funnel containing diethyl ether, ethyl acetate andwater. The organic phase was separated and washed with water and brine.The organic phase was dried over magnesium sulfate. The mixture was thenfiltered and the solvent removed under vacuum. Flash columnchromatography of the residue (silica gel, 40% ethyl acetate/hexanes)provided 123 mg (54%) of the desired carbapenem.

¹ H-NMR (300 MHz, CDCl₃): δ 0.14 (s, 9H), 1.30 (d, J=6.2 Hz, 3H), 1.89(dd, J₁ =J₂ =6.1 Hz, 1H), 3.22-3.44 (complex m, 3H), 4.23-4.34 (complexm, 2H), 4.85 (d, J=6.1 Hz, 2H), 5.20 (ABq, J_(AB) =13.7 Hz, Δν_(AB)=54.5 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H), 7.38 (dd, J=8.6, 1.7 Hz, 1H),7.44 (dd, J=8.4, 1.6 Hz, 1H), 7.66-7.76 (complex m, 4H), 7.88 ppm (d,J=8.7 Hz, 2H).

IR (CHCl₃): 3600(w), 1770(s), 1720(m), 1600(m), 1520(s) cm⁻¹.

UV (CH₃ CN): λ_(max) =320, ε=5000; λ_(max) =270, ε=7200;

EXAMPLE 12 ##STR109##Allyl-(5R,6S)-2-(1-iodomethyl-3-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(15)

To a solution of 107.0 mg (0.225 mmoles) of carbapenem 6 in 4 mlanhydrous CH₂ Cl₂ at -20° C. under a N₂ atmosphere was addedtriethylamine (50.1 μl, 0.36 mmoles), followed by mesyl chloride (22.7μl, 0.29 mmoles). The resulting solution was stirred at -20° under N₂atmosphere for 30 minutes. and then partitioned between CH₂ Cl₂ andice/2.0N aqueous HCl solution. The organic phase was separated andwashed with brine, dried with anhydrous Na₂ SO₄, filtered andconcentrated under vacuum to provide 154.5 mg of a clear film.

¹ H-NMR (300 MHz, CDCl₃): δ 2.88 (s, CH₃ SO₂), 5.68 (s, CH₂ OSO₂).

The crude reaction residue was dissolved in 4 ml anhydrous acetone andsodium iodide (67.5 mg, 0.45 mmoles) was added to the resultingsolution. The solution was stirred at room temperature for 1.5 hrs andthen partitioned between CH₂ Cl₂ and ice/0.5 M aqueous Na₂ S₂ O₃solution. The organic phase was separated and washed with brine, driedwith anhydrous Na₂ SO₄, filtered and concentrated under vacuum toprovide a yellow film. The crude reaction residue was purified by thinlayer chromatography (2×1000μ20×20 cm silica gel, eluted with 4% EtOAcin CH₂ Cl₂) to provide 128.4 mg of the title compound as a yellow foam.

¹ H-NMR (300 MHz CDCl₃): δ 1.51 (d, J=6.8 Hz, CH₃ CHCH), 3.31 (dd,J=9.9, 18.2 Hz, CH₂ CHCH), 3.41 (dd, J=8.7, 18.1 Hz, CH₂ CHCH), 3.46(dd, J=2.7, 8.2 Hz, CH₂ CHCH), 4.33 (dt, J=2.8, 9.2 Hz CHCHCH₂), 4.70(m, CH₂ CH═CH₂ and CH₃ CHCH), 4.87 (s, naphthyl-CH₂ I), 5.3 (m, CH₂CH═CH₂), 5.91 (m, CH₂ CH═CH₂), 7.43 (t, J=7.1, 7.7 Hz, naphthyl-H6),7.59 (d, J=1.7 Hz, naphthyl-H1), 7.67 (t, J=7.0, 7.1 Hz, naphthyl-H7),7.80 (s, naphthyl-H4); 7.76 (d, J=8.2 Hz, naphthyl-H5), 8.07 ppm (d,J=8.1 Hz, naphthyl-H8).

IR (CH₂ Cl₂): 1780, 1745, 1720 cm⁻¹.

EXAMPLE 13 ##STR110## Allyl-(5R,6S)-2-(1-(4-aminopyridinium)methyl-3-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-1-carbapen-2-em-3-carboxylateiodide (16)

To a stirred solution of 58.1 mg (0.099 mmoles) of the iodide 15 in 2 mlanhydrous acetonitrile at 0° C. under a N₂ atmosphere was added 11.2 mg(0.12 mmoles) of 4-aminopyridine as a solid. The resulting reactionsolution was stirred at room temperature under a N₂ atmosphere for 18hours and then was partitioned between CH₂ Cl₂ and ice/H₂ O. The organiclayer was separated, dried with anhydrous Na₂ SO₄, filtered andconcentrated under vacuum to provide 62.9 mg of a yellow film. Theresidue was dissolved in CH₂ Cl₂ and the solution diluted with diethylether. The gummy solid which separated was collected and redissolved inCH₂ Cl₂. Ether was again added and the resulting solid was collected anddried under vacuum to provide 64.3 mg of the title compound as an orangefoam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.47 (d, J=6.77 Hz, CH₃ CHCH), 3.37 (dd,J=9.9, 16.0 Hz, CHCH₂ C), 3.57 (m, CHCH₂ C and CHCHC═O), 4.39 (dt,J=2.1, 9.5 Hz, CHCHCH₂), 4.32 (m, CH₃ CHCH, CH₂ CH═CH₂), 5.25 (m, CH₂CH═CH₂), 5.80 (s, naphthyl-CH₂), 5.88 (m, CH₂ CH═CH₂), 7.18 (d, J=7.1Hz, pyridine H3 and H5), 7.53 (m, naphthyl-H), 7.70 (s, naphthyl-H),7.85 (d, J=8.2 Hz, naphthyl-H), 7.87 (d, J=7.7 Hz, naphthyl-H), 8.05 ppm(d, J=6.3 Hz, pyridine H2 and H6):

IR (CH₂ Cl₂): 1780, 1745, 1720, 1655 cm⁻¹ :

UV(dioxane): λ_(max) =285 nm.

EXAMPLE 14 ##STR111## Allyl-(5R,6S)-2-[1-(2-aminopyridinium)methyl-3-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-1-carbapen-2-em-3-carboxylateiodide (17)

To a solution of iodide 15(67.0 mg, 0.115 mmol) in 2 ml of acetontrilewas added 2-aminopyridine (21.5 mg, 0.229 mmol) in one portion. Afterstirring at room temperature for 18 hours, the mixture was diluted withmethylene chloride and washed successively with water and brine. Drying(MgSO₄) and evaporation left a solid which was dissolved in a minimumvolume of methylene chloride. The product was precipitated by theaddition of ethyl ether and was isolated by centrifugation. Drying invacuo yielded 28.5 mg (45%) of the title compound as a tan solid.

¹ H-NMR (300 MHz, CDCl₃): δ 1.48 (d, J=5.86 Hz, 3H, CH₃), 3.30-3.55 (m,2H, H1), 3.54 (dd, J=7.8, 2.7 Hz, H6), 4.35 (dt, J=2.7, 9.5 Hz, 1H, H5),4.55-4.75 (m, 4H, --OCH₂ C═C), 5.1-5.4 (m, 5H, H8, --C═CH₂), 5.75-6.0(m, 2H, --CH═C), 5.92 (bs, 2H, --CH₂ N), 6.66 (t, J=6.3, 1H, ArH),7.35-7.95 ppm (m, 9H, ArH).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate), 1720 (ester), 1665 cm⁻¹(iminium).

FAB-MS: m/e=554 (M+H).

EXAMPLE 15 ##STR112##Allyl-(5R,6S)-2-{1-[(2-pyridyl)amino]methyl-3-naphthyl}-6-[1R-(allyloxycarbonyloxy)ethyl]-1-carbapen-2-em-3-carboxylate(18)

To a solution of iodide 15 (46.0 mg, 0.0786 mmol) in 2 ml ofacetonitrile was added 2-aminopyridine (9.6 mg, 0.10 mmol) and silvertrifluoromethanesulfonate (32 mg, 0.13 mmol) and the mixture was stirredat room temperature. After 16 hours, the reaction mixture was dilutedwith methylene chloride and filtered. The filtrate was washedsuccessively with water, sat. NH₄ Cl, sat. NaHCO₃, and brine. Drying(MgSO₄) and evaporation left an oil which was purified by preparativeTLC on silica gel (1:4 EtOAc/CH₂ Cl₂) to yield 13 mg (24%) of the titlecompound as an oil.

¹ H-NMR (300 MHz, CDCl₃): δ 1.50 (d, J=6.95 Hz, 3H, CH₃), 3.20-3.45 (m,2H, H1), 3.44 (dd, J=8.1, 2.8 Hz, 1H, H6), 4.31 (dt, J=2.8, 9.4 Hz, 1H,H5), 4.55-4.75 (m, 4H, --OCH₂ C═C), 4.94 (s, 2H, --CH₂ N), 5.1-5.4 (m,5H, H8, --C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 6.43 (d, J=7.9 Hz, 1H, PyH),6.64 (dd, J=7.1, 5.0 Hz, 1H, PyH), 7.44 (dd, J=7.9, 7.1 Hz, 1H, PyH),7.5-8.1 (m, 6H, ArH), 8.15 ppm (br d, J=5 Hz, 1H, PyH).

IR (CHCl₃): 3440 (NH), 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹(ester).

EXAMPLE 16 ##STR113## (5R,6S)-2-(1-(4-Aminopyridinium)methyl-3-naphthyl)-6-[1R-hydroxyethyl]-carbapen-2-em-3-carboxylate.(19)

To a stirred solution of 64.3 mg (0.095 mmoles) of the carbapenem 16 in2 ml anhydous CH₂ Cl₂ and ethyl acetate at 0° under a N₂ atmosphere wasadded a mixture of 14.6 mg (1.26×10⁻⁵ moles) oftetrakis(triphenylphosphine)palladium and 15.6 mg (5.94×10⁻⁵ moles) oftriphenylphosphine, followed by 17.4 μl (0.11 mmoles) of 2-ethylhexanoicacid and 0.218 ml (0.11 mmoles) of a 0.5 M potassium 2-ethylhexanoate inEtOAc solution. The resulting mixture was stirred 0.5 hrs at 0° and 3.5hrs at room temperature under a N₂ atmosphere. A light colouredprecipitate developed after 30 minutes at room temperature. The reactionslurry was then diluted with EtOAc and the solid separated and washed 2×with Et₂ O. The solid was then dried under vacuum and purified byreverse phase-PLC (2×1000μ, 20×20 cm rev. phase silica gel F, eluted at˜5° with 30% THF in H₂ O). The major UV active product bands werecombined and extracted 8 times with CH₃ CN--H₂ O (4:1). The combinedaqueous extracts were washed 3 times with hexanes, filtered through aGelman Acrodisc-CR 0.45μ filter assembly and concentrated under vacuum.The concentrate was lyophilized to give 15.5 mg of the title compound asa white fluffy solid.

¹ H-NMR (300 MHz, D₂ O/THF-d₈ /TSP) δ 1.35 (d, J=6.8 Hz, CH₃ CHCH), 3.18(dd, J=9.5, 17.2 Hz, CH₂ CHCH) 3.46 (dd, J=2.7, 6.1 Hz, CHCHC=O), 3.57(dd, J=8.8, 17.2 Hz, CH₂ CHCH), 4.26 (m, CH₃ CHOH), 4.35 (dt, J=2.0, 9.2Hz, CHCHCH₂), 6.88 (d, J=7.9 Hz, pyridine-H3 and H5), 7.56 (m, 2naphthyl-H), 7.87 (d, J=6.7 Hz, naphthyl-H), 7.95 (m, 3 naphthyl-H),8.20 ppm (d, J=6.9 Hz, pyridine-H2 and H6);

UV(H₂ O): λ_(max) =274, 319 nm.

ECAMPLES 17-33

Operating as described in the previous examples, the following compoundswere analogously prepared:

    __________________________________________________________________________                       EXAMPLE NO.                λ.sub.max.sup.H.sbsp.                                                  2.sup.O                         __________________________________________________________________________     ##STR114##            17                                                                               ##STR115##          M = (-)                                                                             286 nm 319 nm                                    18                                                                               ##STR116##          M = (-)                                                                             287 nm 319 nm                                    19                                                                               ##STR117##          M = K 275 nm 319 nm                                    20                                                                               ##STR118##          M = (-)                                                                             310 nm 286 nm                                    21                                                                               ##STR119##          M = K 318 nm 273 nm                                    22                                                                               ##STR120##          M = K 319 nm                                           23                                                                               ##STR121##          M = (-)                                                                             316 nm                                           24                                                                               ##STR122##          M = (-)                                                                             320 nm                                           25                                                                               ##STR123##          M = (-)                                                                             319 nm                     ##STR124##            26                                                                               ##STR125##          M = (-)                                                                             316 nm                     ##STR126##            27                                                                               ##STR127##          M = (-)                                                                             316 nm 283 nm                                    28                                                                               ##STR128##          M = K 316 nm                                           29                                                                               ##STR129##          M = (-)                                                                             318 nm                     ##STR130##            30                                                                               ##STR131##          M = (-)                                                                             316 nm                     ##STR132##            31                                                                               ##STR133##          M = (-)                                                                             318 nm                                           32                                                                               ##STR134##          M = K  316 nm 286 nm                                   33                                                                               ##STR135##          M = (-)                                                                             307 nm 286                __________________________________________________________________________                                                        nm                    

EXAMPLE 34 ##STR136##Allyl-(5R,6S)-2-[2-(3-methyl-1-imidazolium)methyl-6-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylatetrifluoromethanesufonate (20)

A solution of the carbapenem 8 (53.2 mg, 0.111 mmol) in methylenechloride was cooled to 0° C. and 1-methylimidazole (0.020 mL, 0.24 mmol)was added followed by trifluoromethanesulfonic anhydride (0.022 mL, 0.13mmol). After 1 hour, the reaction mixture was diluted with methylenechloride and washed with water. The organic solution was dried (Na₂ SO₄)and evaporated to provide 79.7 mg of an orange oil.

¹ H-NMR (300 MHz, CDCl₃): δ 1.45 (d, J=6.35 Hz, 3H, CH₃), 3.22 (dd,J=9.89, 18.1 Hz, 1H, H1a), 3.40(dd, J=8.7, 18.1 Hz, 1H, H1b), 3.47 (dd,J=2.7, 7.8 Hz, 1H, H6), 3.79(s, 3H, N-CH₃), 4.29(dt, J=2.7, 9.3 Hz, 1H,H5), 4.50-4.75 (m, 4H, --OCH₂ C═C), 5.05-5.45(m, 5H, H8, --C═CH₂), 5.38(s, 2H, --CH₂ N), 5.7-6.0(m, 2H, --CH═C), 7.19 (s, 1H), 7.23 (s, 1H),7.36 (d, J=8.7 Hz, 1H), 7.42 (d, J=10 Hz, 1H), 7.7-7.8 (m, 2H), 7.75 (s,1 H), 7.82 (s, 1H), 9.07 ppm (s, 1H), 7.82 (s, 1H), 9.07 ppm (s, 1H).

EXAMPLE 35 ##STR137##(5R,6S)-2-[2-(3-methyl-1-imidazolium)methyl-6-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(21)

In an analogous manner to that described in Example 12, carbapenem 20(79.7 mg) was de-allylated to yield the title compound (11.7 mg, 25%) asa yellow lyophilized solid.

¹ H-NMR(300 MHz, 2:1 D₂ O/CD₃ CN): δ 1.65 (d, J=6.2 Hz, 3H, CH₃), 3.50(dd, J=9.8, 16.5 Hz, 1H, H1a), 3.75-3.95 (m, 2H, H1b, H6), 4.20 (s, 3H,--NCH₃), 4.5-4.7 (m, 2H, H5, H8), 5.85 (s, 2H, --CH₂ N), 7.80 (s, 1H),7.84 (s, 1H), 7.75-7.85 (d, 1H, obscured), 7.98 (d, J=8.7 Hz, 1H), 8.20(s, 1H), 8.24 (s, 1H), 8.20-8.25 (d, 1H, obscured), 8.29 ppm (d, J=8.4Hz, 1H).

IR(KBr): 1755 (β-lactam), 1595 cm⁻¹ (carboxylate).

UV(H₂ O): λ_(max) =319 nm; ε=9,7000.

EXAMPLE 36 ##STR138##Allyl-(5R,6S)-2-[2-(3-aminopyridinium)methyl-6-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylatechloride (22)

A solution of the carbapenem 8 (66.2 mg, 0.139 mmol) in CH₂ Cl₂ wascooled to -70° C. and collidine (0.022 mL, 0.17 mmol) was added followedby trifluoromethanesulfonic anhydride (0.026 mL, 0.15 mmol). The paleorange solution was stirred at -70° C. for 30 minutes and then asolution of 3-aminopyridine in CH₂ Cl₂ (4.1M, 0.074 mL, 0.30 mmol) wasadded dropwise. The reaction mixture was allowed to warm gradually to-20° C. during 35 minutes and was then hydrolyzed with sat. NH₄ Cl-H₂ O(1:1). The reaction mixture was partitioned between EtOAc and sat. NH₄Cl-H₂ O (1:1) and the organic phase was washed with water and brine.Drying (Na₂ SO₄) and evaporation gave 84 mg of a brown oil. Thismaterial was dissolved in CH₂ Cl₂ (1 mL) and pipetted into ethyl ether(2 mL) in a centrifuge tube. The resulting solid was isolated bycentrifugation and dried in vacuo to yield 72 mg (88%) of the pyridiniumsalt.

¹ H-NMR(300 MHz, CDCl₃): δ 1.46 (d, J=6.16 Hz, 3H, CH₃), 3.15-3.45 (m,2H, H1), 3.46 (dd, J=2.5, 8.0 Hz, 1H, H6), 4.3 (br t, J=9 Hz, 1H, H5),4.4-4.8 (m, 4H, --OCH₂ C═C), 5.0-5.5 (m, 5H, H8, --C═CH₂), 5.7-6.0 (m,4H, --CH═C, --CH₂ N), 7.2-7.9 (m, 9H), 8.45 ppm (broad s, 1H).

EXAMPLE 37 ##STR139##(5R,6S)-2-[2-(3-Aminopyridinium)methyl-6-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(23)

In an analogous manner to that described in Example 12, carbapenem 22(72 mg, 0.12 mmol) was de-allylated to yield the title compound (12.5mg, 24%) as a pale yellow lyophilized solid.

¹ H-NMR (300 MHz, 2:1 D₂ O/CD₃ CN): δ 1.64 (d, J=6.2 Hz, 3H, CH₃), 3.49(dd, J=9.8, 16.5 Hz, 1H, H1a), 3.75-3.95 (m, 2H, H1b, H6), 4.5-4.7 (m,2H, H5, H8), 6.05 (s, 2H, --CH₂ N), 7.8 (d, J=7.7 Hz, 1H), 7.9-8.05 (m,3H), 8.15-8.35 (m, 4H), 8.4-8.5 ppm (m, 2H).

IR(KBr): 1750 (β-lactam), 1585 cm⁻¹ (carboxylate).

UV(H₂ O): λmax=313 nm; ε=15,700.

EXAMPLE 38 ##STR140##Allyl-(5R,6S)-2-(2-formyl-6-naphthyl)-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(24)

To a stirring solution of oxalyl chloride (0.023 mL, 0.24 mmol) in 1.5mL of methylene chloride at -70° C. was added neat dimethylsulfoxide(0.023 mL, 0.32 mmol). After 5 minutes., a solution of the alcohol 8(113 mg, 0.237 mmol) in 0.5 mL of methylene chloride was added dropwise.The reaction mixture was stirred at -70° C. for 15 minutes and thentriethylamine (0.091 mL, 0.65 mmol) was added. The temperature wasmaintained at -70° C. for 5 minutes more, and was then allowed to warmgradually to 0° C. during 2 hours. The reaction mixture was quenchedwith pH 7 phosphate buffer and was then diluted with ethyl acetate andwashed successively with pH 7 phosphate buffer, water (2x) and brine.Drying (MgSO₄) and evaporation gave 105 mg (93%) of the title aldehydeas an oil which required no purification.

¹ H-NMR (300 MHz, CDCl₃): δ 1.51 (d, J=5.61 Hz, 3H, CH₃), 3.25-3.50 (m,3H, H6, H1), 4.36 (dt, J=2.75, 9.4 Hz, 1H, H5), 4.55-4.8 (m, 4H, --OCH₂C═C), 5.1-5.4 (m, 5H, H8, --C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 7.56 (d,J=8.61 Hz, 1H, ArH), 7.8-8.0 (m, 4H, ArH), 8.32 (s, 1H, ArH), 10.16 ppm(s, 1H, CHO).

EXAMPLE 39 ##STR141## Allyl-(5R,6S)-2-{6-[E-2-(2-pyridyl)vinyl]-2-naphthyl}-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate (25)

To a solution of the aldehyde 24 (105 mg, 0.221 mmol) in 2.5 mL ofacetonitrile was added (2-picolyl)triphenylphosphonium iodide (129 mg,0.34 mmol) followed by diisopropylethylamine (0.050 mL, 0.29 mmol). Thereaction mixture was stirred at room temperature for 5 hours and wasthen diluted with ethyl acetate and washed with sat. NH₄ Cl, sat.NaHCO₃, and brine. Drying (MgSO₄), evaporation, and purification bypreparative TLC on silica gel yielded 58 mg (48%) of the title compoundas an oil.

¹ H-NMR(300 MHz, CDCl₃): δ 1.51 (d, J=6.29 Hz, 3H, CH₃), 3.25-3.5 (m,2H, H1), 3.45 (dd, J=8.4, 2.8 Hz, 1H, H6), 4.33 (dt, J=2.8, 9.3 Hz, 1H,H5), 4.55-4.8 (m, 4H, --OCH₂ C═C), 5.1-5.5 (m, 5H, H8, --C═CH₂),5.75-6.0 (m, 2H, --CH═C), 7.15-7.90 (m, 11H, ArH, CH═CH), 8.63 ppm (d,J=4.82 Hz, 1H, ArH).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate), 1725 (ester), 1590 cm⁻¹(olefin).

FAB-MS: m/e=551 (M+H).

EXAMPLE 40 ##STR142## Potassium (5R,6S)-2-{6-[E-2-pyridyl)vinyl]-2-naphthyl}-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(26)

To solution of carbapenem 25 (29 mg, 0.053 mmol) in ethyl acetate (1mL)-methylene chloride (1 mL) were added in sequence triphenylphosphine(4 mg, 0.016 mmol), 2-ethylhexanoic acid (0.0080 mL, 0.053 mmol),potassium 2-ethylhexanoate (0.50 M solution in EtOAc, 0.105 mL, 0.053mmol) and tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol). Thereaction mixture was stirred at room temperature for 2 hours and wasthen pipetted into a centrifuge tube containing ethyl acetate. Theresulting solid was isolated by centrifugation, washing twice with ethylacetate. Purification by reverse phase preparative TLC (4:1 H₂ O/THF)yielded 7.0 mg (28%) of the title compound as a white lyophilized solid.

¹ H-NMR (300 MHz, d₈ -THF/D₂ O): δ 1.4 (d, J=6 Hz, 3H, CH₃), 3.1-3.25(m, 1H, H1a), 3.5-3.65 (m, 2H, H1b, H6), 4.25-4.45 (m, 2H, H5, H8),7.3-8.1 (m, 11H, ArH, CH═CH), 8.6 ppm (bs, 1H, ArH).

IR(KBr): 1750 (β-lactam), 1590 cm⁻¹ (carboxylate).

UV(H₂ O): λ_(max) =349 nm; ε=28,500.

EXAMPLE 41 ##STR143## Allyl-(5R, 6S)-2-{6-[E-2-(N-methyl-2-pyridinium)vinyl]-2-naphthyl}-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-carboxylate trifluoromethanesulfonate (27)

To a solution of the carbapenem 25 (28 mg, 0.051 mmol) in 1.5 mL ofmethylene chloride was added methyl trifluoromethanesulfonate (6.0 μL0.053 mmol). After 6 hours at room temperature, the solvent wasevaporated in vacuo leaving the title compound as an orange solid.

¹ H-NMR (300 MHz, CDCl₃): δ 1.49 (d, J=6.11 Hz, 3H, CH₃), 3.15-3.55 (m,3H, H1, H6), 4.15 (s, 3H, N--CH₃), 4.33 (br t, J=9.3 Hz, 1H, H5),4.5-4.85 (m, 4H, --OCH₂ C═C), 5.1-5.45 (m, 5H, H8, --C═CH₂), 5.8-6.0 (m,2H, --CH═C), 7.2-8.2 ppm (m, 12H, ArH, CH═CH).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate, 1725 (ester), 1615 cm⁻¹(olefin).

EXAMPLE 42 ##STR144## (5R,6S)-2-{6-[E-2-(N-Methyl-2-pyridinium)vinyl]2-naphthyl}-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(28)

Carbapenem 27 was de-allylated in a manner analogous to that describedin Example 12 to give the title compound (7.0 mg, 31% overall) as ayellow lyophilized solid.

IR (KBr): 1750 (β-lactam), 1610 cm⁻¹ (carboxylate).

UV (H₂ O): λmax=368 nm (ε=24,000).

EXAMPLES 43-46

Operating as described in the preceding examples, the followingcompounds were analogously prepared:

    __________________________________________________________________________                          EXAMPLE NO.                        λ                                                                      .sub.max.sup.H.sb                                                             sp.2.sup.O           __________________________________________________________________________     ##STR145##           43                                                                                      ##STR146##               319 nm                                     44                                                                                      ##STR147##               335 nm                                     45                                                                                      ##STR148##               390, 315 nm           ##STR149##           46                                                                                      ##STR150##               318                  __________________________________________________________________________                                                             nm               

EXAMPLE 47 ##STR151## 2-Bromo-6-(N-succinimido)-naphthalene (29)

A solution of 2-amino-6-bromonaphthalene (0.565 g, 2.54 mmol) andsuccinic anhydride (0.508 g, 5.08 mmol) in 13 mL of benzene was refluxedfor 1.5 hours. The resulting precipitate was isolated by filtration,washing with additional benzene. After drying in vacuo, 0.780 g of asolid was obtained which was dissolved in 12 mL of acetic anhydridealong with sodium acetate (0.595 g, 7.26 mmol) and refluxed for 3 hours.After cooling to room temperature, the reaction mixture was quenchedwith 3 mL of water and was evaporated to dryness under high vacuum.Purification by flash chromatography through 150 g of silica gel (1:4EtOAc/CH₂ Cl₂) yielded 0.670 g (86%) of the title compound as a whitesolid.

¹ H-NMR (300 MHz, CDCl₃): δ 2.95 (bs, 4H), 7.41 (dd, J=8.8, 1.9 Hz, 1H),7.59 (dd, J=8.8, 1.7 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.84(d, J=8.8 Hz, 1H), 8.04 ppm (s, 1H).

FAB-MS: m/e=504,506 (M+H).

EXAMPLE 48 ##STR152## 2-Bromo-6-(N-pyrrolidino)naphthalene (30)

To a solution of 2-bromo-6-(N-succinimido)-naphthalene 29 (0.670 g, 2.20mmol) in 7 mL of 2-methoxyethyl ether at 0° C. was added borontrifluoride etherate (0.567 mL, 4.61 mmol) followed by dropwise additonof a solution of sodium borohydride (0.166 g, 4.39 mmol) in 6 mL of2-methoxyethyl ether. After 1 hour the reaction mixture was carefullyhydroylzed with water followed by saturated NaHCO₃ and was thenpartitioned between methylene chloride and saturated NaHCO₃. The organicphase was dried (MgSO₄) and evaporated to leave a solid which waspurified by flash chromatography through 75 g of silica gel (1:4EtOAc/CH₂ Cl₂) to yield 0.540 g (88%) of the title compound as a whitesolid.

¹ H-NMR (300 MHz, CDCl₃): δ 2.0-2.1 (m, 4H, --CH₂ CH₂ --), 3.35-3.45 (m,4H, --CH₂ NCH₂ --), 6.73 (bs, 1H), 7.01 (dd, J=9.0, 2.3 Hz, 1H), 7.39(dd, J=8.8, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H),7.88 ppm (d, J=1.8 Hz, 1H).

UV(CH₃ CN): λmax=252 nm; ε=8,000, 218 nm; ε=20,800.

FAB-MS: m/e=276,278 (M+H).

EXAMPLE 49 ##STR153##(3S,4R)-1-(Allyloxycarbonyltriphenylphosphoranylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[2-(N-pyrrolidino)-6-naphthylcarbonyl]methylazetidin-2-one(31)

To a mixture of bromide 30 (0.260 g, 0.945 mmol) and magnesium turnings(32 mg, 1.3 mmol) in 3 mL of tetrahydrofuran was added 1,2-dibromoethane(0.010 mL) and the reaction mixture was sonicated briefly in anultrasonic bath to initiate the Grignard formation. The mixture washeated at 50° C. for 10 minutes and was then stirred at room temperaturefor 3 hours. The Grignard solution thus prepared was added dropwise to asolution of 0.539 g (0.759 mmol) of(3S,4R)-1-(allyloxycarbonyltriphenylphosphorylidene)methyl-3-[1R-(allyloxycarbonyloxy)ethyl]-4-[(2-pyridylthio)carbonyl]methyl-azetidin-2-one,3, in 8 mL of tetrahydrofuran at 0° C. After 2 hours, the reactionmixture was hydrolyzed with saturated NH₄ Cl solution, diluted with alarge volume of ethyl acetate, and washed successively with saturatedNH₄ Cl, 1N NaOH, H₂ O, and brine. Drying (MgSO₄) and evaporation gave ayellow oil which was separated by flash chromatography through 75 g ofsilica gel (7:3 EtOAc/hexane) to yield 0.411 g (68%) of the titlecompound as a yellow-green oil.

¹ H-NMR (300 MHz, CDCl₃): δ 1.16 (d, J=6.11 Hz, 3H, CH₃), 2.0-2.15 (m,4H, --CH₂ CH₂ --), 3.35-3.50 ppm (m, 4H, --CH₂ --N--CH₂ --).

IR (CHCl₃): 1745 (β-lactam, carbonate), 1665 (ketone), 1620 cm⁻¹(ylide).

FAB-MS: m/e=795 (M+H).

EXAMPLE 50 ##STR154## Allyl-(5R,6S)-2-[2-(N-pyrrolidino)-6-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(32)

The phosphorane 31 prepared in the preceding example (0.411 g, 0.518mmol) was dissolved in 18 mL of p-xylene along with several crystals ofp-hydroquinone and the solution was heated to reflux (138° C.). After 3hours the solution was cooled to room temperature, the solvent wasevaporated in vacuo, and the residue was purified by flashchromatography through 30 g of silica gel (3:2 EtOAc/hexane) to yield0.177 g (66%) of the title compound as a yellow-green foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.50 (d, J=6.34 Hz, 3H, CH₃), 2.0-2.1 (m,4H, --CH₂ CH₂ --), 3.25-3.50 (m, 7H, H1, H6, --CH₂ NCH₂ --), 4.27 (dt,J=2.7, 9.3 Hz, 1H, H5), 4.6-4.8 (m, 4H, --OCH₂ C═C), 5.1-5.4 (m, 5H, H8,--C═CH₂), 5.8-6.0 (m, 2H, --CH═C), 6.7-7.7 ppm (m, 6H, ArH).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate), 1720 (ester), 1625 cm⁻¹(C═C).

UV (CH₃ CN): λ_(max) =387, 246 nm.

FAB-MS: m/e=517 (M+H).

EXAMPLE 51 ##STR155## Potassium(5R,6S)-2-[2-(N-pyrrolidino)-6-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(33)

To a solution of the carbapenem 32 (35 mg, 0.068 mmol) in ethyl acetate(1 mL)-methylene chloride (1 mL) were added sequentiallytriphenylphosphine (5 mg, 0.02 mmol), 2-ethylhexanoic acid (0.012 mL,0.080 mmol), potassium 2-ethylhexanoate (0.5M solution in EtOAc, 0.17mL, 0.085 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007mmol). The reaction mixture was stirred at room temperature for 1.5hours and was then pipetted into a centrifuge tube containing ethylacetate (2 mL). The precipitate was isolated by centrifugation washingonce with ethyl ether. Separation by reverse phase preparative TLC (4:1H₂ O/THF) yielded 8.0 mg (30%) of the title compound as an off-whitelyophilized solid.

¹ H-NMR (300 MHz, D₂ O): δ 1.63 (d, J=6.41 Hz, 3H, CH₃), 2.30-2.45 (m,4H, --CH₂ CH₂ --), 3.46 (dd, J=9.9, 16.5 Hz, 1H, Hla), 3.65-3.85 (m, 6H,Hlb, H6, --CH₂ NCH₂ --), 4.50-4.65 (m, 2H, H6, H8), 7.18 (s, 1H), 7.43(dd, J=9.1, 1.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H),8.01 (s, 1H), 8.07 ppm (d, J=9.1 Hz, 1H).

IR(KBr): 1750 (β-lactam), 1625 (C═C), 1600 cm⁻¹ (carboxylate).

UV (H₂ O): λ_(max) =342 nm (ε=15,000), 246 nm.

EXAMPLE 52 ##STR156##Allyl-(5R-6S)-2-[2-(N-methyl-N-pyrrolidinium)-6-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylatetrifluoromethane sulfonate (34)

To a solution of carbapenem 32 (0.177 g, 0.343 mmol) in 6 mL ofmethylene chloride was added methyl trifluoromethanesulfonate (0.043 mL,0.38 mmol). After stirring at room temperature for 6 hours the volatileswere evaporated in vacuo to leave the title compound as a foam.

¹ H-NMR (300 MHz, CDCl₃): δ 1.47 (d, J=6.35 Hz, 3H, CH₃), 2.15-2.40 (m,4H, --CH₂ CH₂ --), 3.2-3.55 (m, 2H, Hl), 3.42 (s, 3H, N--CH₃), 3.52 (dd,J=7.8, 2.7 Hz, 1H, H6), 3.90-4.05, 4.30-4.45 (m, 4H, --CH₂ --N--CH₂ --),4.30-4.45 (H5, obscured), 4.5-4.8 (m, 4H, --OCH₂ C═C), 5.1-5.4 (m, 5H,H8, --C═CH₂), 5.75-6.0 (m, 2H, --CH═C), 7.53 (d, J=8.7 Hz, 1 H), 7.72(d, J=9.2 Hz, 1 H), 7.84 (s, 1H), 7.92 (d, J=8.9 Hz, 2H), 8.17 ppm (s,1H).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹ (ester).

EXAMPLE 53 ##STR157## (5R,6S)-2-[2-(N-methyl-N-pyrrolidinium)-6-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(35)

Carbapenem 34, prepared in the preceding example, was de-allylated in amanner analogous to that described in Example 51 to yield 39 mg (28% fortwo steps) of the title compound as a yellow lyophilized solid.

1_(H) --NMR (300 MHz, D₂ O): δ1.35(d, J=6.41 Hz, 3H, CH₃), 2.3-2.5 (m,4H, --CH₂ CH₂ --), 3.13 (dd, J=9,8, 16.7 Hz, 1H, Hla), 3.45-3.60 (m, 2H,Hlb, H6), 3.52 (s, 3H, NCH₃), 4.05-4.20, 4.25-4.40 (m, 4H, --CH₂--N--CH₂), 4.25-4.40 (m, 2H, H5, H8), 7.59 (dd, J=8.9, 2.7 Hz, 1H), 7.7(d, 1H, partially obscured), 7.83 (s, 1H), 7.92 (d, J=8.9 Hz, 1H), 8.07(d, J=9.3 Hz, 1H), 8.22 ppm (d, J=2.4 Hz, 1H).

IR (KBr): 1755 (β-lactam), 1600 cm⁻¹ (carboxylate).

UV (H₂ O): λ_(max) =318nm (Ε=13,500), 276 nm.

FAB-MS: m/e=407 (M+H).

EXAMPLE 54 ##STR158## Allyl-(5R,6S)-2-[1-(N-pyrrolidino)-7-naphthyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate(36)

In a manner analogous to that described in Examples 47-50, but startingwith 1-amino-7-bromo-naphthalene [H.H. Hodgson and R.E. Dean, J. Chem.Soc. 818 (1950)], the title compound was obtained as an orange oil.

¹ H-NMR (300 MHz, CDCl₃)): δ1.51 (d, J=6.3 Hz, 3H, CH₃), 1.95-2.10 (m,4H, --CH₂ CH₂ --), 3.25-3.40 (m, 6H, Hl, --CH₂ NCH₂ --), 3.45 (dd,J=8.5, 2.8 Hz, 1H, H6), 4.31 (dt, J=2.8, 9.3 Hz, 1H, H5), 4.6-4.8 (m,4H, --OCH₂ C═C), 5.1-5.4 (m, 5H, H8, --C═CH₂), 5.8-6.0 (m, 2H, --CH═C),6.9-7.0(m, 1H), 7.3--7.5 (m, 3H), 7.74 (d, J=8.7 Hz, 1H), 8.20 ppm (s,1H).

IR (CHCl₃): 1780 (β-lactam), 1745 (carbonate), 1725 cm⁻¹ (ester).

UV (CH₃ CN): λ_(max) =307 nm.

FAB-MS: m/e=517 (M+H).

EXAMPLE 55 ##STR159## Potassium(5R,6S)-2-[1-(N-pyrrolidino)-7-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(37)

Carbapenem 36 (60 mg, 0.12 mmol) was de-allylated in a manner analogousto that described in Example 51 to yield 14.8 mg (30%) of the titlecompound as a lyophilized solid.

IR (KBr): 1750 (β-lactam), 1590 cm⁻¹ (carboxylate).

UV (H₂ O): λ_(max) =295 nm; ε=7,800.

EXAMPLE 56 ##STR160## (5R,6S)-2-[1-(N-methyl-N-pyrrolidinium)-7-naphthyl]-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate(38)

In a manner analogous to that described in Examples 52-53, thecarbapenem 36 (57 mg, 0.11 mmol) gave the title compound (18 mg, 40%) asan off-white lyophilized solid.

¹ H-NMR (300 MHz, D₂ O): δ 1.33 (d, J=6.47 Hz, 3H, CH₃), 2.20-2.55 (m,4H, --CH₂ CH₂ --), 3.18 (dd, J=9.7, 16.2 Hz 1H, H1a), 3.25-3.6 (m, 2H,H1b, H6), 3.73 (s, 3H, NCH₃), 4.2-4.5 (m, 6H, H5, H8, --CH₂ NCH₂ --),7.5-7.6 (m, 2H), 7.95 (d, J=8.5 Hz, 1H), 8.0-8.1 (m, 2H), 8.19 ppm (s,1H).

IR (KBr): 1755 (β-lactam), 1595 cm⁻¹ (carboxylate).

UV (H₂ O): λ_(max) =320 nm; ε=8,900, 280 nm; e=11,000.

What is claimed is:
 1. A compound of the formula: ##STR161## wherein: Ris H or CH₃ ;R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that one but not more than oneR^(a) is selected from Type I substituents and zero to three R^(a)radicals are selected from Type II substituents; wherein the Type Isubstituents are: I. (a) ##STR162## where A is (CH₂)_(m) --Q--(CH₂)_(n),where m is 0 to 6 and n is 1 to 6 and Q is a covalent bond, O, S, SO,SO₂, NH, --SO₂ NH--, --NHSO₂ --, --CONH--, --NHCO--, --SO₂ N(C₁ -C₄alkyl)--, --N(C₁ -C₄ alkyl)SO₂ --, --CON(C₁ -C₄ alkyl)--, --N(C₁ -C₄alkyl)CO--, --CH═CH--, --CO--, --OC(O)--, --C(O)O-- or N(C₁ -C₄ alkyl),and (CH₂)_(m) is attached to the naphthyl moiety; ##STR163## is a 5- or6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclicheterocycle, the heterocycle containing a first nitrogen in an aromatic5- or 6-membered first ring, with attachment of the heterocycle to A byway of said first nitrogen and said first nitrogen is quaternary byvirtue of the attachment and ring bonds, with the first ring containing0 or 1 or either O or S, with the first ring containing 0 to 3additional nitrogen atoms, with the first ring optionally fused to a 3-or 4-membered moiety to form the optional second ring, with the themoiety containing at least one carbon atom, with the moiety containing 0or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms,and with the moiety being saturated or unsaturated and the second ringaromatic or non-aromatic; R^(c) is R^(a) as defined under II below,hydrogen, or --NR^(Y) R^(z) (where R^(Y) and R^(z) are defined in IIbelow), but independently selected from R^(a) and from each other ifmore than one R^(c) is present and is attached to a carbon ring atom ora nitrogen heteroatom the valency of which is not satisfied by the ringbonds; I. (b) ##STR164## where ##STR165## is a 5- or 6-memberedmonocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle,the heterocycle containing a first nitrogen in an aromatic 5- or6-membered first ring, with said first nitrogen quaternary by virtue ofa substituent R^(d) in addition to the ring bonds thereto, with saidfirst nitrogen neutral in the absence of a substituent R^(d), withattachment of the heterocycle to A' by way of a carbon atom of a ring,with the first ring containing 0 or 1 of either O or S, with the firstring containing 0 to 2 additional nitrogen atoms, with the first ringoptionally fused to a 3- or 4-membered moiety to form the optionalsecond ring, with the moiety containing at least one carbon atom, withthe moiety containing 0 or 1 of either O or S, with the moietycontaining 0 to 2 nitrogen atoms, and with the moiety being saturated orunsaturated and the second ring aromatic or non-aromatic; R^(c) is asdefined above; R^(d) is hydrogen, NH₂, O⁻ or C₁ -C₄ alkyl (where thealkyl group is optionally mono-substituted with R^(q) as defined underIIc below); A' is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 6 and n is 0to 6, Q is as given above except that when m and n are both O then Q isnot a covalent bond and (CH₂)_(m) is attached to the naphthyl moiety; I.(c) --A_(p) --N⁺ R^(Y) (R^(w))₀₋₁ (R^(z)) where R^(y) and R^(z) are asdefined under II below, R^(y) and R^(z) may further be together a C₂ -C₄alkylidene radical to form a ring (optionally mono-substituted withR^(q) as defined below) interrupted by N(O)R^(e) or N⁺ (R^(e))₂ (whereR^(e) is hydrogen, C₁ -C₄ alkyl or C₁ -C₄ alkyl mono-substituted withR^(q) as defined below), R^(w) is hydrogen, C₁₋₄ alkyl, O⁻, NH₂ orabsent in which case the nitrogen is neutral, R^(w), R^(y) and R^(z) mayfurther together form a C₅ -C₁₀ tertiary alkylidene radical which withN⁺ forms a bicyclic ring, where the tertiary alkylidene radical isoptionally mono-substituted with R^(q) as defined below and where thetertiary carbon of the tertiary alkylidene radical is optionallyreplaced with nitrogen, N⁺ R^(e) (where R^(e) is as defined above), orN⁺ --O⁻, p is 0 or 1, and A is as defined above; I. (d) ##STR166## where##STR167## is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or10-membered bicyclic heterocycle, the heterocycle containing a firstnitrogen in a first ring, with the first ring saturated or unsaturatedand non-aromatic, with the first nitrogen quaternary by virtue of one ortwo substituents R^(d) in addition to the ring bonds thereto, with thefirst nitrogen alternatively neutral by virtue of zero or onesubstituent R^(d) in addition to the ring bonds thereto, with attachmentof the heterocycle to A' by way of a carbon atom or non-quaternarynitrogen atom of a ring, with the first ring containing in addition tocarbon and the first nitrogen 0 to 1 of a member selected from the groupconsisting of the non-quaternary nitrogen of attachment, O, S, S(O),S(O)₂ and NR^(e) where R^(e) is as defined above, with the first ringoptionally fused to a 2-, 3- or 4-membered moiety to form the optionalsecond ring, with the moiety optionally containing in addition to carbonthe non-quaternary nitrogen of attachment, and with the moiety saturatedor unsaturated and the second ring non-aromatic; R^(d) is as definedabove and where more than one R^(d) is present on a nitrogen, at leastone R^(d) is hydrogen or C₁ -C₄ alkyl; A' is as defined above; and p isas defined above; R^(q) is as defined below;and wherein the Type IIsubstituents are: II.(a) a trifluoromethyl group: --CF₃ ; (b) a halogenatom: --Br, --Cl, --F, or --I; (c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl,wherein the alkyl is optionally mono-substituted by R^(q), where R^(q)is a member selected from the group consisting of --OH, --OCH₃, --CN,--C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂ N(CH₃)₂,--SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) is hydrogen,alkali metal, methyl or phenyl), tetrazolyl (where the point ofattachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);(d) a hydroxy group:--OH; (e) a carbonyloxy radical: --O(C═O)R^(s), where R^(s) is C₁₋₄alkyl or phenyl, each of which is optionally mono-substituted by R^(q)as defined above;(f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) whereR^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ --, to form a ring(where the ring is optionally mono-substituted with R^(q) as definedabove);(g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s)is as defi49d above; (h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) whereR^(y) and R^(z) are as defined above; (i) azido: N₃ (j) a formamidogroup: --N(R^(t))(C═O)H, where R^(t) is H or C₁₋₄ alkyl, and the alkylthereof is optionally mono-substituted by R^(q) as defined above;(k) a(C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t)) (C═O)C₁₋₄ alkyl, whereR^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; (l) a (C₁ -C₄ alkoxy)carbonylamino radical: --N(R^(t)) (C═O)OC₁₋₄ alkyl, where R^(t) is asdefined above, and the alkyl group is also optionally mono-substitutedby R^(q) as defined above; (m) a ureido group:--N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R_(y) R^(z) are as definedabove; (n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) andR^(t) are as defined above; (o) a cyano group: --CN; (p) a formyl oracetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ; (q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂C₁₋₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; (r) carbonyl radical: --(C═O)R^(s), where R^(s) is asdefined above; (s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; (t) a (C₁ -C₄alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where the alkyl isoptionally mono-substituted by R^(q) as defined above; (u) a carbamoylradical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are as definedabove; (v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical inwhich the nitrogen atom may be additionally substituted by a C₁ -C₄alkyl group: --(C═O) --N(OR^(y))R^(z) where R^(y) and R^(z) are asdefined above, except they may not be joined together to form a ring;(w) a thiocarbamoyl group: --(C═S)N(R^(y))R^(z) where R^(y) and R^(z)are as defined above; (x) carboxyl: --COOM^(b), where M^(b) is asdefined above; (y) thiocyanate: --SCN; (z) trifluoromethylthio: --SCF₃ ;(aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above; (ab) an anionic function selected from the groupconsisting of: phosphono [P═O(OM^(b))₂ ]; alkylphosphono{P═O(OM^(b))--[O(C₁ -C₄ alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄alkyl)]; phosphoramido [P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x)]; sulfino (SO₂ M^(b)); sulfo (SO₃ M^(b)); acylsulfonamides selectedfrom the structures CONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂NM^(b) CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S, and in which from 1 to 2additional carbon atoms are optionally replaced by a nitrogenheteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;(ac) C₅ -C₇ cycloalkyl group inwhich one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH or N(C₁ -C₄ alkyl) and in which one additionalcarbon atom may be replaced by NH or N(C₁ -C₄ alkyl), and in which atleast one carbon atom adjacent to each heteroatom has both of itsattached hydrogen atoms replaced by one oxygen thus forming a carbonylmoiety and there are one or two carbonyl moieties present in the ring;(ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above; (ae) C₂ -C₄ alkynyl radical,optionally mono-substituted by one of the substituents (a) to (ac)above; (af) C₁ -C₄ alkyl radical; (ag) C₁ -C₄ alkyl mono-substituted byone of the substituents (a)-(ac) above; (ah) a 2-oxazolidinonyl moietyin which the point of attachment is the nitrogen atom of theoxazolidinone ring, the ring oxygen atom is optionally replaced by aheteroatom selected from S and NR^(t) (where R^(t) is as defined above)and one of the saturated carbon atoms of the oxazolidinone ring isoptionally mono-substituted by one of the substituents (a) to (ag)above; M is selected from:(i) hydrogen; (ii) a pharmaceuticallyacceptable esterifying group or removable carboxyl protecting group;(iii) an alkali metal or other pharmaceutically acceptable cation; or(iv) a negative charge which is balanced by a positively charged group.2. The compound of claim 1 wherein R¹ is hydrogen and R² is (R)--CH₃CH(OH)-- or (R)--CH₃ CH(F)--.
 3. The compound of claim 2 wherein the oneR^(a) radical selected from Type I substituents is a Type I(a)substituent of the formula: ##STR168## where X=O, S, or NR^(c).
 4. Thecompound of claim 2 wherein the one R^(a) radical selected from Type Isubstituents is a Type I. (b) substituent of the formula: ##STR169##where X=O, S, or NR^(c) and X'+O or S. For structures of Type I. (b),where R^(c) and/or A' are shown to have indefinite positions, they areindependently attached to any carbon atom of the ring.
 5. The compoundof claim 2 wherein the one R^(a) radical selected from Type Isubstituents is a Type I. (c) substituent of the formula: ##STR170##where W is O, S, NR^(e), N(O)R^(e), SO, SO₂ or N⁺ (R^(e))₂ and W' is N⁺R^(e) or NO.
 6. The compound of claim 2 wherein the one R^(a) radicalselected from Type I substituents is a Type I. (d) substituent of theformula: ##STR171##
 7. The compound of claim 2 wherein said R^(c) whereattached to a ring carbon atom is selected from the group consisting of--NH₂, --SCH₃, --SOCH₃, --CH₂ OH, --(CH₂)₂ OH, --OCH₃, --COOM^(b), --CH₂COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --SO₃ M^(b),--CH₂ SO₃ M^(b), --CH₂ CH₂ SO₃ M^(b), --Br, --Cl, --F, --I, --CH₃, CH₂CH₃, CH₂ CONH₂ and CH₂ CON(C₁ -C₄ alkyl).
 8. The compound of claim 2wherein said R^(c) where attached to neutral ring nitrogen atom isselected from the group consisting of --CH₂ OH, --(CH₂)₂ OH, --CH₂COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --CH₂ SO₃ M^(b),--CH₂ CH₂ SO₃ M^(b), --CH₃, CH₂ CH₃, CH₂ CONH₂ and CH₂ CON(C₁ -C₄alkyl).
 9. The compound of claim 2 wherein the R^(d) groups optionallyattached to the compound are independently selected from hydrogen,--CH₃, CH₂ CH₃, --CH₂ CH₂ CH₃, --CH₂ COOM^(b), --CH₂ SO₃ M^(b), --NH₂ orO.sup.(×).
 10. The compound of claim 2 wherein the A spacer is selectedfrom --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ --,--OCH₂ CH₂ --, --SOCH₂ --, --SO₂ CH₂ --, --SCH₂ CH₂ --, --SOCH₂ CH₂ --,--SO₂ CH₂ CH₂ --, --NHCH₂ CH₂ --, --N(CH₃)CH₂ CH₂ --, --CH₂ N(CH₃)CH₂CH₂ --, --CONHCH₂ CH₂ --, --SO₂ NHCH₂ CH₂ --, --COCH₂ --, --CH═CHCH₂--or --CH₂ OCH₂ CH₂ --.
 11. The compound of claim 2 wherein the A'spacer is selected from --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH₂CH₂ CH₂ CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --, --SO₂ CH₂ --, --SCH₂ CH₂ --,--SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂ CH₂ --, --N(CH₃)CH₂ CH₂ --,--CH₂ N(CH₃)CH₂ CH₂ --, --CONHCH₂ CH₂ --, --SO₂ NHCH₂ CH₂ --, --COCH₂--, --CH═CHCH₂ --, --CH₂ OCH₂ CH₂ --, --O--, --S--, --NH--, --SO₂ --,--SO₂ NH--, --CONH--, --CH═CH--, --CH₂ S--, --CH₂ NH--, --CONHCH₂ --or--SO₂ NHCH₂ --.
 12. The compound of claim 2 wherein one to three R^(a)radicals are independently selected from Type II substituents of theformula:

    ______________________________________                                        --OCH.sub.3        --OCH.sub.2 CO.sub.2 Na                                    --OCH.sub.2 CH.sub.2 OH                                                                          --CF.sub.3                                                 --F                --Cl                                                       --Br               --I                                                        --OH               --OCOCH.sub.3                                              --OCONH.sub.2      --SCH.sub.3                                                --SOCH.sub.3       --SO.sub.2 CH.sub.3                                        --SCH.sub.2 CH.sub.2 OH                                                                          --SOCH.sub.2 CH.sub.2 OH                                   --SO.sub.2 NH.sub.2                                                                              --SO.sub.2 N(CH.sub.3).sub.2                               --NHCHO            --NHCOCH.sub.3                                             --NHCO.sub.2 CH.sub.3                                                                            --NHSO.sub.2 CH.sub.3                                      --CN               --CHO                                                      --COCH.sub.3       --COCH.sub.2 OH                                            --CH═NOH       --CH═NOCH.sub.3                                        --CH═NOCH.sub.2 CO.sub.2 H                                                                   --CH═NOCMe.sub.2 CO.sub.2 H                            --CH═NOCMe.sub.2 CO.sub.2 Me                                                                 --CO.sub.2 CH.sub.2 CH.sub.2 OH                            --CONH.sub.2       --CONHCH.sub.3                                             --CON(CH.sub.3).sub.2                                                                            --CONHCH.sub.2 CN                                          --CONHCH.sub.2 CONH.sub.2                                                                        --CONHCH.sub.2 CO.sub.2 H                                  --CONHOH           --CONHOCH.sub.3                                            tetrazolyl         --CO.sub.2 Na                                              --SCF.sub.3        --PO.sub.3 NaH                                             --CONHSO.sub.2 Ph  --CONHSO.sub.2 NH.sub.2                                    --SO.sub.3 Na      --SO.sub.2 NHCN                                            --SO.sub.2 NHCONH.sub.2                                                                          --CH═CHCN                                              --CH═CHCONH.sub.2                                                                            --CH═CHCO.sub.2 Na                                     --C.tbd.C--CONH.sub.2                                                                            --C.tbd.C--CN                                              --CH.sub.2 OH      --CH.sub.2 N.sub.3                                         --CH.sub.2 CO.sub.2 Na                                                                           --SO.sub.2 CH.sub.2 CH.sub.2 OH or                                            --CH.sub.2 I.                                              ______________________________________                                    


13. A compound of the formula: ##STR172## where M and R^(a) are:

    ______________________________________                                        M      R.sup.a               R.sup.a Position                                 ______________________________________                                        (--)                                                                                  ##STR173##           1                                                (--)                                                                                  ##STR174##           5                                                (--)                                                                                  ##STR175##           6                                                (--)                                                                                  ##STR176##           7                                                (--)                                                                                  ##STR177##           8                                                (--)                                                                                  ##STR178##           1                                                (--)                                                                                  ##STR179##           5                                                (--)                                                                                  ##STR180##           6                                                (--)                                                                                  ##STR181##           7                                                (--)                                                                                  ##STR182##           8                                                (--)                                                                                  ##STR183##           1                                                (--)                                                                                  ##STR184##           5                                                (--)                                                                                  ##STR185##           6                                                (--)                                                                                  ##STR186##           7                                                (--)                                                                                  ##STR187##           8                                                (--)                                                                                  ##STR188##           7                                                (--)                                                                                  ##STR189##           7                                                (--)                                                                                  ##STR190##           7                                                (--)                                                                                  ##STR191##           7                                                (--)                                                                                  ##STR192##           7                                                        ##STR193##           7                                                K                                                                                     ##STR194##           7                                                K                                                                                     ##STR195##           7                                                K                                                                                     ##STR196##           7                                                (--)                                                                                  ##STR197##           6                                                (--)                                                                                  ##STR198##           7                                                (--)                                                                                  ##STR199##           7                                                (--)                                                                                  ##STR200##           7                                                (--)                                                                                  ##STR201##           7                                                (--)                                                                                  ##STR202##           7                                                (--)                                                                                  ##STR203##           1                                                (--)                                                                                  ##STR204##           1                                                (--)                                                                                  ##STR205##           7                                                (--)                                                                                  ##STR206##           1                                                (--)                                                                                  ##STR207##           7                                                (--)                                                                                  ##STR208##           1                                                (-- )                                                                                 ##STR209##           1                                                (--)                                                                                  ##STR210##           7                                                (--)                                                                                  ##STR211##           7                                                (--)                                                                                  ##STR212##           7                                                (--)                                                                                  ##STR213##           7                                                (--)                                                                                  ##STR214##           1                                                (--)                                                                                  ##STR215##           1                                                (--)                                                                                  ##STR216##           1                                                (--)                                                                                  ##STR217##           7                                                (--)                                                                                  ##STR218##           7                                                H                                                                                     ##STR219##           7                                                (--)                                                                                  ##STR220##           1                                                (--)                                                                                  ##STR221##           1                                                (--)                                                                                  ##STR222##           1                                                (--)                                                                                  ##STR223##           1                                                (--)                                                                                  ##STR224##           7                                                (--)                                                                                  ##STR225##           7                                                K                                                                                     ##STR226##           1                                                K                                                                                     ##STR227##           1                                                (--)                                                                                  ##STR228##           1                                                (--)                                                                                  ##STR229##           7                                                (--)                                                                                  ##STR230##           7                                                (--)                                                                                  ##STR231##           7                                                (--)                                                                                  ##STR232##           7                                                K                                                                                     ##STR233##           7                                                K                                                                                     ##STR234##           7                                                (--)                                                                                  ##STR235##           7                                                (--)                                                                                  ##STR236##           1                                                ______________________________________                                                         R.sup.a                R.sup.a'                                               Posi-                  Posi-                                 M    R.sup.a     tion    R.sup.a'       tion                                  ______________________________________                                        (--) CN          1                                                                                      ##STR237##    7                                     (--) SOCH.sub.3  1                                                                                      ##STR238##    7                                     (--) CO.sub.2 K  1                                                                                      ##STR239##    7                                     (--) CO.sub.2 K  1                                                                                      ##STR240##    7                                     (--)                                                                                ##STR241## 1                                                                                      ##STR242##    7                                     (--)                                                                                ##STR243## 1                                                                                      ##STR244##    7                                     (--) SO.sub.3 K  1                                                                                      ##STR245##    7                                     (--) CO.sub.2 K  1                                                                                      ##STR246##    7                                     (--) SO.sub.3 K  1                                                                                      ##STR247##    6                                     (--) SO.sub.3 K  5                                                                                      ##STR248##    7                                     (--) CHO         1                                                                                      ##STR249##    7                                     ______________________________________                                        M      R.sup.a               R.sup.a Position                                 ______________________________________                                        (--)                                                                                  ##STR250##           1                                                (--)                                                                                  ##STR251##           1                                                (--)                                                                                  ##STR252##           1                                                (--)                                                                                  ##STR253##           1                                                (--)                                                                                  ##STR254##           1                                                        ##STR255##           1                                                K                                                                                     ##STR256##           5                                                K                                                                                     ##STR257##           7                                                (--)                                                                                  ##STR258##           1                                                (--)                                                                                  ##STR259##           1                                                K                                                                                     ##STR260##           1                                                K                                                                                     ##STR261##           7                                                K                                                                                     ##STR262##           1                                                (--)                                                                                  ##STR263##           1                                                K                                                                                     ##STR264##           8                                                K                                                                                     ##STR265##           5                                                K                                                                                     ##STR266##           7 or                                             (--)                                                                                  ##STR267##           
 5.                                              ______________________________________                                    


14. A pharmaceutical composition for antibacterial use comprising anantibacterially effective amount of a compound of claim 1 and apharmaceutically acceptable carrier therefor.
 15. A method of treatingbacterial infections in human or animal subjects in need of suchtreatment comprising administering to such subject an antibacteriallyeffective amount of a compound of claim
 1. 16. A pharmaceuticalcomposition for antibacterial use comprising an antibacteriallyeffective amount of a compound of claim 1, an inhibitorily effectiveamount of a DHP inhibitor, and, optionally, a pharmaceuticallyacceptable carrier therefor.
 17. The pharmaceutical compositionaccording to claim 18 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.
 18. A method of treating bacterial infections in human or animalsubjects in need of such treatment comprising coadministering to suchsubject an antibacterially effective amount of a compound of claim 1 andan inhibitorily effective amount of a DHP inhibitor.
 19. The methodaccording to claim 17 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclclopropane-carcoxamide)-2-heptenoicacid.